WO2009156767A2 - Improvements to microplate sealing - Google Patents

Improvements to microplate sealing Download PDF

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Publication number
WO2009156767A2
WO2009156767A2 PCT/GB2009/050753 GB2009050753W WO2009156767A2 WO 2009156767 A2 WO2009156767 A2 WO 2009156767A2 GB 2009050753 W GB2009050753 W GB 2009050753W WO 2009156767 A2 WO2009156767 A2 WO 2009156767A2
Authority
WO
WIPO (PCT)
Prior art keywords
heat block
resiliently deformable
plate
well plate
heat
Prior art date
Application number
PCT/GB2009/050753
Other languages
French (fr)
Other versions
WO2009156767A3 (en
Inventor
Philip Steven Robinson
Original Assignee
Kbiosciences 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 Kbiosciences Limited filed Critical Kbiosciences Limited
Publication of WO2009156767A2 publication Critical patent/WO2009156767A2/en
Publication of WO2009156767A3 publication Critical patent/WO2009156767A3/en

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    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C66/00—General aspects of processes or apparatus for joining preformed parts
    • B29C66/80—General aspects of machine operations or constructions and parts thereof
    • B29C66/81—General aspects of the pressing elements, i.e. the elements applying pressure on the parts to be joined in the area to be joined, e.g. the welding jaws or clamps
    • B29C66/814—General aspects of the pressing elements, i.e. the elements applying pressure on the parts to be joined in the area to be joined, e.g. the welding jaws or clamps characterised by the design of the pressing elements, e.g. of the welding jaws or clamps
    • B29C66/8145—General aspects of the pressing elements, i.e. the elements applying pressure on the parts to be joined in the area to be joined, e.g. the welding jaws or clamps characterised by the design of the pressing elements, e.g. of the welding jaws or clamps characterised by the constructional aspects of the pressing elements, e.g. of the welding jaws or clamps
    • B29C66/81459—General aspects of the pressing elements, i.e. the elements applying pressure on the parts to be joined in the area to be joined, e.g. the welding jaws or clamps characterised by the design of the pressing elements, e.g. of the welding jaws or clamps characterised by the constructional aspects of the pressing elements, e.g. of the welding jaws or clamps being a filled deformable bladder, e.g. bladder filled with oil, with granules or with a meltable solid material
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    • 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
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    • B29C65/02—Joining or sealing of preformed parts, e.g. welding of plastics materials; Apparatus therefor by heating, with or without pressure
    • B29C65/18—Joining or sealing of preformed parts, e.g. welding of plastics materials; Apparatus therefor by heating, with or without pressure using heated tools
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    • B29C66/53—Joining single elements to tubular articles, hollow articles or bars
    • B29C66/534—Joining single elements to open ends of tubular or hollow articles or to the ends of bars
    • B29C66/5346—Joining single elements to open ends of tubular or hollow articles or to the ends of bars said single elements being substantially flat
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    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C66/00—General aspects of processes or apparatus for joining preformed parts
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    • B29C66/814—General aspects of the pressing elements, i.e. the elements applying pressure on the parts to be joined in the area to be joined, e.g. the welding jaws or clamps characterised by the design of the pressing elements, e.g. of the welding jaws or clamps
    • B29C66/8145—General aspects of the pressing elements, i.e. the elements applying pressure on the parts to be joined in the area to be joined, e.g. the welding jaws or clamps characterised by the design of the pressing elements, e.g. of the welding jaws or clamps characterised by the constructional aspects of the pressing elements, e.g. of the welding jaws or clamps
    • B29C66/81455—General aspects of the pressing elements, i.e. the elements applying pressure on the parts to be joined in the area to be joined, e.g. the welding jaws or clamps characterised by the design of the pressing elements, e.g. of the welding jaws or clamps characterised by the constructional aspects of the pressing elements, e.g. of the welding jaws or clamps being a fluid inflatable bag or bladder, a diaphragm or a vacuum bag for applying isostatic pressure
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    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
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    • B29C66/80—General aspects of machine operations or constructions and parts thereof
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    • B29C66/814—General aspects of the pressing elements, i.e. the elements applying pressure on the parts to be joined in the area to be joined, e.g. the welding jaws or clamps characterised by the design of the pressing elements, e.g. of the welding jaws or clamps
    • B29C66/8145—General aspects of the pressing elements, i.e. the elements applying pressure on the parts to be joined in the area to be joined, e.g. the welding jaws or clamps characterised by the design of the pressing elements, e.g. of the welding jaws or clamps characterised by the constructional aspects of the pressing elements, e.g. of the welding jaws or clamps
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    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
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    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2105/00—Condition, form or state of moulded material or of the material to be shaped
    • B29K2105/06—Condition, form or state of moulded material or of the material to be shaped containing reinforcements, fillers or inserts
    • B29K2105/16—Fillers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2827/00—Use of polyvinylhalogenides or derivatives thereof as mould material
    • B29K2827/12—Use of polyvinylhalogenides or derivatives thereof as mould material containing fluorine
    • B29K2827/18—PTFE, i.e. polytetrafluorethene, e.g. ePTFE, i.e. expanded polytetrafluorethene
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2995/00—Properties of moulding materials, reinforcements, fillers, preformed parts or moulds
    • B29K2995/0012—Properties of moulding materials, reinforcements, fillers, preformed parts or moulds having particular thermal properties
    • B29K2995/0013—Conductive
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2995/00—Properties of moulding materials, reinforcements, fillers, preformed parts or moulds
    • B29K2995/0037—Other properties
    • B29K2995/007—Hardness
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29L—INDEXING SCHEME ASSOCIATED WITH SUBCLASS B29C, RELATING TO PARTICULAR ARTICLES
    • B29L2031/00—Other particular articles
    • B29L2031/756—Microarticles, nanoarticles

Definitions

  • This invention relates to improvements for sealing microplates used for scientific purposes, and more particularly, improvements relating to apparatus for sealing microplates and methods for sealing microplates.
  • Microtitre plates are typically formed of moulded plastic material, and are rectangular in shape having an array of wells, each well having a circular aperture in the top surface of the plate.
  • the use of the microtitre plate (also known as the microplate or micro well plate), traditionally based on an array of 8 x 12 wells (i.e. having 96 wells) in a footprint of approximately 80mm x 120mm has gained universal acceptance. More recently the need for cost containment and throughput increases has given rise to the creation of 384 well plates (based on a 16 x 24 array of wells), 1536 well plates (based on a 32 x 48 array of wells) and higher still densities.
  • PCR polymerase chain reaction
  • the micro well plate is received on a heated sample block which heats and cools the wells from below, cycling between a low temperature and a high temperature (the maximum temperature typically being around 9O 0 C to 98 0 C).
  • thermocyclers have means for clamping the sealing lid against the top surface of the micro well plate to seal the sealing lid against the micro well plate. Condensation of vapour inside the wells may be prevented by heating the sealing lid, to maintain it at substantially the same temperature as the sample block below the micro well plate, such that there is no temperature differential across the height of the wells of the micro well plate (this is sometimes referred to as 'heated-lid technology').
  • the seal provided is only temporary, the seal only being maintained whilst the thermocycler device applies a clamping force between the sealing lid and the micro well plate.
  • micro well plates require a removable, semi-permanent seal.
  • Such semi-permanent seals are required for applications wherein the seal needs to be maintained even after the micro well plate has been removed from sealing apparatus, for example for storage of liquids in micro well plates for high density compound storage.
  • Semi-permanent seals may also be required for micro well plates used in high density high throughput screening assays.
  • a type of semipermanent seal used in the prior art is heat-sealable film. These are applied to the micro well plates using thermal sealer apparatus. After removal of the micro well plate from the thermal sealer apparatus, the seal provided by the heat-sealable film is maintained until a user peels off or punctures the sealing film.
  • thermal sealers are available. These are available from Thermo Abgene (Epsom, Surrey) as the ALPS® 300 and 3000 and from Agilent Velocity 11 (Menlo Park, California). These instruments for the most part satisfy the needs of the current microplate sealing market. There are however a number of disadvantages where these instruments are not well suited.
  • the currently available thermal sealers are notably not suitable for sealing in cases when the plate density increases to above 384 wells per plate (i.e. these thermal sealers are not suitable for sealing 1536 well plates) and when the injection moulded plates have inconsistently moulded wells.
  • inconsistently moulded wells we mean where the injection mould has not filled perfectly or where there is wear in the mould tool, resulting in a non-flat top sealing surface of the plate.
  • the current thermal sealer instruments rely on the ability of the combination of pressure and heat to seal, thus minimising the effect of badly moulded plates.
  • the principles of the process is to apply a seal normally made of a laminate of two differing melting point polymers to a plate and then to apply, either manually or in an automated fashion, heat via a preheated flat plate made of either copper or aluminium.
  • the lower melting point polymer then melts with the top of the plate being sealed thus creating a bond and a seal.
  • thermal glue is also incorporated into the seal itself.
  • 1536 well plates have such small wells that the combination of heat and pressure melts the plastic to the point that the wells are closed or badly mis-shaped.
  • apparatus for sealing a micro well plate having a plurality of wells, each well having an aperture in a surface of the micro well plate comprising a heat block, at least a portion of the heat block being resiliently deformable, wherein said at least a portion of the heat block is contactable in use with a film to be sealed to the micro well plate to seal the plurality of apertures, the apparatus further comprising heating means for heating the heat block in use to seal the film to the micro well plate by melt-sealing the film to the micro well plate.
  • the heat block is resiliently deformable, such that it can conform to the top surface of a micro well plate to be sealed. It can be used to seal a film onto a micro well plate, the micro well plate having a plurality of apertures in its top surface. If the top surface of the micro well plate is not flat, the resiliently deformable heat block will conform to the top surface of the micro well plate, allowing the film to fully contact the top surface of the micro well plate and to form a strong, robust seal with the micro well plate. The apparatus therefore provides improved sealing over prior art thermal sealers.
  • the entire heat block may be resiliently deformable, or alternatively a portion of the heat block may be deformable.
  • the film attaches to a surface of the micro well plate, around each aperture, by melting of the film or a portion of the film to the surface of the micro well plate.
  • the heat block is heatable to a sufficiently high temperature by the heating means in order to melt the film onto the micro well plate.
  • the apparatus is used to provide a removable, semi-permanent seal wherein the film remains sealed to the micro well plate, after removal of the micro well plate from the apparatus, until the seal is physically removed or broken by a user or by de-sealing apparatus. The film thus remains sealed to the micro well plate even after the heat source has been removed from the film (i.e. after the heat block has been moved away from the film).
  • the resiliently deformable heat block or heat block portion is contacted with the film for of the order of a few seconds or less in order to seal the film to the micro well plate.
  • said at least a portion of the heat block is contacted with the film for less than 5 seconds, preferably less than 3 seconds, or preferably around 1 second or less.
  • thermo cyclers there are examples of thermal cyclers in the prior art which use heated lid technology to seal micro well plates while they are in the thermal cycler, undergoing thermal cycling.
  • EP 1 045 038 describes a thermo cycler which uses heated lid technology and has a high pressure heated lid comprising a screw mechanism, a heated rigid metal plate and an elastic insulating gasket which serves for tight pressuring of a polypropylene sealing film to the top surface of the multi well plate in the thermal cycler.
  • the heated lid seals the wells during thermocycling and heating of the lid prevents condensation of vapour on the inside of the lid.
  • the heated lid would only be heated up to around 100°C (so as not to heat the micro well plate contents above the maximum temperature needed for the PCR process) which is well below the melting temperature of the polypropylene film.
  • the polypropylene film of the prior art heated lid technology used in the thermal cycler of EP 1 045 038 is temporarily forced tightly against the top surface of the micro well plate during thermal cycling and only seals the plate whilst pressure is applied between the film and the plate.
  • the thermal cycler of EP 1 045 038 the film is not melt-sealed to the micro well plate. In such prior art thermal cyclers, the seal is only maintained whilst screw mechanism holds the lid against the micro well plate.
  • said resiliently deformable heat block or heat block portion is made from a material selected from a group comprising silicon rubber, carbon enriched silicon rubber, fluoroelastomer, Viton ®, Alfas ® FEPM, Dyneon ®, FPM/FKM, PTFE and Tecnoflon ®.
  • the resiliently deformable heat block or heat block portion comprises a resiliently deformable material incorporating a substance that increases the overall thermal conductivity of the resiliently deformable heat block or heat block portion. The substance increases the overall ability of the resiliently deformable heat block or heat block portion to transfer heat.
  • the resiliently deformable heat block or heat block portion comprises a resiliently deformable material incorporating a material of higher thermal conductivity than the resiliently deformable material.
  • the resiliently deformable material may be impregnated throughout with material of high thermal conductivity such as a heat- conducting additive, or the resiliently deformable material may have material of high thermal conductivity embedded therein. This helps allow the heat block or heat block portion to reach the temperature necessary to melt the film to the micro well plate. Increasing the overall thermal conductivity of the heat block or heat block portion increases the temperature that it can be heated to, allowing the apparatus to melt the film by applying a high temperature to the film over a short time.
  • the resiliently deformable heat block or heat block portion comprises a resiliently deformable material enriched with a substance having a higher thermal conductivity than the resiliently deformable material.
  • the resiliently deformable heat block or heat block portion comprises a resiliently deformable material enriched with metal powder.
  • the resiliently deformable heat block or heat block portion is made from a material enriched with aluminium powder, copper powder, gold powder, silver powder, nickel powder or graphite powder.
  • the resiliently deformable heat block or heat block portion comprises a resiliently deformable material having a material of higher thermal conductivity than the resiliently deformable material embedded therein.
  • the resiliently deformable heat block or heat block portion has at least one metal strip or metal wire embedded therein.
  • the resiliently deformable heat block or heat block portion has a plurality of metal wires embedded therein, each metal wire being oriented with its axis perpendicular to the planar face of the resiliently deformable heat block or heat block portion that faces the micro well plate during sealing. The perpendicularly oriented wires improve conductance of heat to the film.
  • the heat block includes a cavity therein, the cavity containing a fluid in use.
  • the heat block includes a flexible membrane adjacent said cavity, such that during sealing of a micro well plate the fluid can flow within the cavity, the flexible membrane conforming to irregularities in the top surface of the micro well plate.
  • the fluid flows within the cavity in response to pressure exerted on it through the flexible membrane, improving moulding of the shape of the heat block to the apertured surface of the micro well plate.
  • the fluid within the heat block improves the overall heat transfer properties of the heat block, increasing the temperature that the heat block and film can be heated to.
  • the fluid is oil, and more preferably the fluid is silicone oil.
  • the boiling point of the fluid is above the temperature required to melt the film.
  • the boiling point of the fluid is 12O 0 C or above.
  • the boiling point of the fluid is 15O 0 C or above, or 16O 0 C or above.
  • the heating means for heating the heat block may be located within the fluid filled cavity or alternatively external to the fluid filled cavity but in thermal contact with the fluid filled cavity.
  • the resiliently deformable heat block or heat block portion is heatable to a temperature sufficient to seal the film to the micro well plate by melt-sealing the film to the micro well plate.
  • the resiliently deformable heat block or heat block portion has an overall thermal conductivity such that it is heatable to a temperature sufficient to seal the film to the micro well plate by melt-sealing the film to the micro well plate.
  • said resiliently deformable heat block or heat block portion is heatable to at least 120 0 C. In other words, the temperature of the heat block or heat block portion can reach at least 120 0 C in use during sealing.
  • said resiliently deformable heat block or heat block portion is heatable to at least 150°C.
  • said resiliently deformable heat block or heat block portion is heatable to at least 160 0 C.
  • said resiliently deformable heat block or heat block portion is made of a material with a Shore hardness on the A scale of between 10 and 100 inclusive, or more preferably, of between 30 and 50 inclusive.
  • the resiliently deformable heat block is capable of withstanding a temperature of up to at least 150°C, but more preferably 200°C, and most preferably 250 0 C.
  • the heating means for heating the heat block are located, in use, within the deformable heat block or heat block portion.
  • the apparatus further comprises a heat plate, wherein the heat plate is heated in use and contacts said resiliently deformable heat block or heat block portion during sealing of a micro well plate.
  • the heat plate may be a rigid heat plate.
  • said resiliently deformable heat block or heat block portion is attached to the heat plate in use.
  • the heat plate comprises a vacuum plate.
  • the vacuum plate has a plurality of through holes, the through holes being in communication with a suction pump, the resiliently deformable heat block or heat block portion having a plurality of through holes. This enables the heat block to be used to pick up the film and place it on top surface of the micro well plate, via the vacuum force applied through the holes in the vacuum plate and the heat block or heat block portion.
  • the vacuum plate comprises a copper vacuum plate.
  • the means for heating the heat block or heat block portion comprises a resistive heater.
  • the apparatus further comprises means for moving the heat block or heat block portion up and down, in use, relative to a micro well plate.
  • the moving device can move the heat block or heat block portion towards or away from the micro well plate in use.
  • the apparatus further comprises means for moving a micro well plate up and down, in use, relative to the heat block or heat block portion.
  • the moving device can move the micro well plate towards or away from the heat block or heat block portion in use.
  • the apparatus further comprises force applying means for applying a force between the heat block and a micro well plate.
  • the heat block or heat block portion is heated, in use, via heat conduction.
  • the heat block or heat block portion is heated by contacting it, in use, with a heated body or plate.
  • apparatus for sealing a micro well plate comprising a heat block, at least a portion of the heat block being resiliently deformable, the apparatus further comprising heating means for heating the heat block in use,
  • the heat block is heated by heating means located within the heat block.
  • the heat block is heated by a rigid heat plate, the heat plate being heated by heating means.
  • the heating means for heating the rigid heat plate may be located within the heat plate or adjacent the heat plate in use.
  • the heat block is attached to the underside, in use, of the rigid heat plate. In this way, the heat block is heated by the heat plate, and the resiliently deformable heat block or heat block portion can be brought into contact with the film to be sealed to the micro well plate.
  • the resiliently deformable heat block or heat block portion is placed on a top surface of the film and the heated rigid heat plate is contacted with the heat block, to heat the heat block.
  • the method further comprises the step of applying a force between the heat block and the micro well plate.
  • the film comprises a polymer film or foil which is sealable to a micro well plate when heated.
  • the rigid heat plate comprises a vacuum plate, the vacuum plate having a plurality of through holes, the plurality of through holes being in communication with a suction pump, the resiliently deformable heat block comprising a plurality of through holes, wherein in step (ii) the resiliently deformable heat block is used to pick up the film using suction force and to place the film on the top surface of the micro well plate.
  • Figure 1 shows a perspective view of a composite soft block for use in an embodiment of the invention
  • Figure 2A-2D show schematic diagrams depicting sealing of a microtitre plate using prior art thermal sealers and using a soft heat block according to the present invention
  • figure 2A shows a well-moulded microtitre plate being sealed in a conventional manner using a prior art thermal sealer
  • figure 2B shows a badly moulded plate being sealed in a conventional manner using a prior art thermal sealer
  • figure 2C shows a badly moulded plate prior to application of a soft block / heater block to seal the microtitre plate
  • figure 2D shows a badly moulded plate being sealed with a soft block / heater assembly
  • Figure 3 shows a perspective view of a substrate block part of a composite block according to another embodiment of the invention.
  • Figure 4 shows a perspective view of the substrate block of figure 3 with a soft block attached to it;
  • Figure 5 shows a perspective view of a substrate block of a composite block with a liquid filled cavity according to a further embodiment of the invention
  • Figure 6 shows a perspective view of the substrate block of figure 5 having a flexible membrane placed on it;
  • FIG 2C shows a schematic diagram of a badly moulded microtitre plate 15 being sealed with a film 16 using a prior art thermal sealer 20.
  • Figure 2C demonstrates the problems of such prior art sealers.
  • the thermal sealer 20 has a heated metal flat plate 21. If the microtitre plate 15 is badly moulded, and has a non-flat top surface as shown in figure 2C, a sealing film 16 cannot be reliably sealed to the top surface of the plate, as in some places, the film does not contact the top surface of the plate during the sealing operation. Because of the uneven surface of the badly moulded microtitre plate 15, a reliable seal cannot be formed between the film 16 and the microtitre plate 15.
  • Embodiments of the present invention are described below by way of example only. These examples represent the best ways of putting the invention into practice that are currently known to the applicant although they are not the only ways in which this could be achieved.
  • the composite block 10 comprises a soft block 1 1 of material that is attached to a thermally conducting heater block 12.
  • the soft block 1 1 is made of a material that is resiliently deformable, is able to conduct heat, and that is able to withstand high temperatures that are required in sealing microtitre plates.
  • the resiliently deformable soft block 1 1 may be made of a number of suitable materials, including silicon rubber, carbon enriched silicon rubber, Viton ®, Alfas ® FEPM, Dyneon ®, fluoroelastomers (also known as FPM/FKM), nitrile, PTFE or Tecnoflon ®.
  • the soft block 11 is made of a soft material, having a shore hardness measured on the A scale of between 10-100 inclusive and capable of withstanding up to at least 150 0 C, but more preferably 200 0 C and most preferably 250°C in temperature.
  • the resiliently deformable material may be enriched with an additive of high thermal conductivity, such as a metal powder, for example aluminium, copper, gold, silver or nickel powder.
  • a metal powder for example aluminium, copper, gold, silver or nickel powder.
  • the resiliently deformable material may be enriched with graphite powder.
  • the thermal conductivity of the soft block can be increased by embedding metal wire or metal strips within the resiliently deformable material.
  • the soft block 11 is attached to the underside of a heater block 12. Between the soft block 11 and the heater block 12 is a soft block substrate plate 14, which is a plate typically made of aluminium or copper on which the soft block 1 1 is formed during manufacture of the soft block 1 1.
  • the soft block substrate 14 on which the soft block 1 1 has been formed is mounted to the heater block 12 in order to mount the soft block 1 1 to the heater block 12.
  • the heater block 12 is thermally conducting and is heated using one or more resistive heaters. Preferably four 125 Watt cartridge heaters or one or more silicone flat elements are used to heat the heater block 12.
  • the heater block 12 is attached to a thermally insulated block 13, which stops heat transferring away from the heater block 12 and soft block 11 , and away from the film and microtitre plate to be sealed.
  • the apparatus may include a support (not shown), , such as a rotary plate support, for holding/supporting the microtitre plate to be sealed whilst pressure is applied between the composite block 10 and the microtitre plate.
  • a support such as a rotary plate support
  • FIGS. 2C and 2D schematic diagrams showing sealing of a microtitre well plate 15 using a composite block 10 of the present invention are shown.
  • the microtitre plate 15 has a plurality of wells 15a.
  • a planar seal or film 16 is placed over the apertures of a microtitre plate.
  • the heated composite block 1 1 is then brought into contact with the film 16 and pressure is applied between the soft block 11 and the microtitre plate 15.
  • the soft block 11 on the underside of the heater block 12 is resiliently deformable, and therefore deforms, conforming to the shape of the top surface of the plate 15, as shown in figure 2D. Therefore, if sealing a badly moulded plate 15, in which the top surface of the plate is not flat, the soft block 11 conforms to the shape of the top surface of the plate 15, enabling a strong seal to be formed between the film 16 and the top surface of the plate 15.
  • a resiliently deformable soft block 11 to contact the film 16 gives superior performance to a rigid heater block (schematic diagrams showing sealing using prior art thermal sealers are shown in figures 2A and 2B).
  • the soft block 11 is able to conform to the shape of the plate 15, such that the plate can be reliably sealed despite having imperfections in its surface flatness.
  • a further advantage of the present invention is that it allows reliable sealing of 1536 well plates, as 1536 well plates could not be reliably sealed using prior art sealing apparatus.
  • Well plates typically have a total area of around 80-85 mm by 120-125 mm.
  • Each well in a 1536 well plate typically has an aperture diameter in the surface of the plate of around 1.7 mm.
  • the surface of the soft block 1 1 which engages with the film in use during sealing is preferably rectangular in shape and is a solid rectangular or substantially solid rectangular surface, with no or substantially no voids.
  • the surface of the soft block 11 that engages with the film in use is at least 85 x 125 mm in size, therefore it covers the whole of the well plate, covering each well aperture in the surface of the well plate.
  • 384 and 96 well plates can be sealed using this apparatus.
  • 384 well plates have wells having an aperture diameter of around 3.6 mm and 98 well plates have wells having an aperture diameter of around 4.8-5 mm.
  • the apparatus of the present invention is therefore suitable for sealing plates having a plurality of apertures, each aperture having a diameter of less than 10 mm, and preferably less than 5 mm.
  • a further advantage of the present invention is that any solvent or reagents that have been spilled on the top surface of the microtitre plate 15 will be forced off the top surface of the plate 15 whilst pressure is applied between the soft block 1 1 and the plate 15.
  • any solvent or reagents spilled on the top surface of the plate 15 would be trapped between the top surface of the plate 15 and the film 16; when the heated flat plate 21 is applied, the solvent or reagent would be heated, causing it to boil and form bubbles between the top surface of the plate 15 and the film 16, thus creating areas where the film 16 is not fully sealed to the plate 15.
  • the use of the soft block 11 of the present invention overcomes this problem by forcing the spilled liquid off the top surface of the plate 15.
  • the film 16 may be any film used in conventional thermal sealers.
  • the film may be a planar seal made of a laminate of two differing melting point polymers or a foil / polymer laminate.
  • the soft block 1 1 need not be formed on a substrate plate 14, in which case a resiliently deformable soft block 1 1 could be mounted directly onto a heater block 12.
  • a soft block which is separate from a rigid heater block may be used instead of using a composite block wherein a soft block is mounted to the underside of a rigid heater block.
  • the soft block may be placed on top of a microtitre plate on which a film has been located.
  • Heater means such as a rigid heater block may then be brought into contact with the soft block 11 to seal the film to the microtitre plate. Therefore, the soft block need not be mounted to a rigid heater block, but may comprise a separate part of the apparatus, which is brought into contact with the rigid heater block during sealing in order to heat the soft block.
  • the heater block 12 may be a copper vacuum plate. This aids heat transfer to the front of the soft block 1 1.
  • the copper vacuum plate has one or more through holes which lead to a vacuum chamber comprising a vacuum or suction pump.
  • the soft block also comprises one or more through holes. When the suction pump is in use, this provides a vacuum force enabling the film to be picked up using the soft block and to be placed on the top surface of the microtitre plate.
  • An advantage of using a copper vacuum plate is therefore that a suction force can be created which can be used to pick the film up and transfer it to the top of the micro well plate to be sealed. This system is more reliable in picking up and transferring the sealing film than prior art systems.
  • heating means such as one or more resistive heaters, embedded in the soft block 11 for heating the soft block.
  • the soft block may be attached to means for applying a force between the soft block and the microtitre plate.
  • an individual, separate soft block with embedded heating means may be placed on top of a film, which has been placed on the top surface of a microtitre plate, and the apparatus may apply force between the heated soft block and the microtitre plate to seal the microtitre plate.
  • a Teflon covered aluminium or copper platen is provided as a substrate block 1 14.
  • a layer of thermally conductive closed cell silicone sponge rubber such as Thermacool R TM R-
  • the layer of silicone sponge rubber acts as a soft block 1 11 , similar to the soft block 1 1 of figure 1.
  • the thermal conductivity of the closed cell silicone sponge rubber increases with compression of the material, the material having a thermal conductivity of 0.65
  • the layer of closed cell silicone sponge rubber 11 1 is glued to the substrate block 1 14 using a thermally conductive adhesive; for example, a thermally conductive acrylic transfer adhesive may be used as the adhesive, allowing heat to transfer from the substrate block to the soft block 1 11.
  • a thermally conductive adhesive for example, a thermally conductive acrylic transfer adhesive may be used as the adhesive, allowing heat to transfer from the substrate block to the soft block 1 11.
  • the substrate block 1 14 would be connected below a heater block (not shown in figures 3 or 4), the heater block containing heater elements.
  • the heater block would be connected underneath an insulating block (not shown in figures 3 or 4), which insulates the mechanics of the thermal sealer apparatus from the heat generated by the heater block.
  • the substrate block 1 14 has four suction cups or vacuum cups 130, one at each corner of the rectangular face of the substrate block 1 14 which faces towards the apertured surface of the microtitre plate in use.
  • the vacuum cups 130 link with vacuum flow channels incorporated in the substrate block 114 and heater block, which lead to a vacuum or suction pump, which provides a vacuum force enabling the film to be picked up using the substrate block 1 14 and placed on the top surface of the microtitre plate.
  • the thermal conductivity of the resiliently deformable material can be increased by embedding metal wire or metal strips within the resiliently deformable material.
  • a layer of silicone rubber having monel or aluminium metal wires embedded therein can be glued to the substrate block using a thermally conductive adhesive, such as thermally conductive acrylic transfer adhesive.
  • the wires are orientated perpendicular to the planar surface of the silicone rubber block which contacts the sealing film in use.
  • a suitable material, having 900 wires per square inch of silicone rubber oriented perpendicular to the rubber planar face, is available from Kemtron Ltd, Essex UK.
  • the ends of the wires in the silicone rubber contact both the metal substrate block and the sealing film, assisting transfer of heat from the heater block to the sealing film, whilst providing a soft block which deforms to the surface of the microtitre plate.
  • wires of metals other than monel or aluminium may be used to embed the soft block.
  • the heated block contains a liquid filled cavity.
  • the composite block includes a Teflon covered aluminium or copper platen or substrate block 214.
  • the substrate block 214 is machined to produce a cavity 240 having four side walls 241.
  • a cavity having a depth of around 5 mm is machined in the substrate block 214.
  • the cavity 240 is filled with a liquid 242, such as a silicone based oil.
  • a phenyl methyl silicone oil called 702 Silicone Oil may be used.
  • a flexible membrane 243 is placed across the opening of the cavity 240 and sealed to the side walls 241 of the cavity 240.
  • a suitable material for the flexible membrane is Thermacool R TM TC3006 from Saint-Gobain, which is a very soft ceramic-filled silicone elastomer, having a thermal conductivity of around 1.1 VWmK.
  • the flexible membrane is thick enough such that it is durable, and not liable to be punctured, but is thin enough such that it transfers heat to the sealing film sufficiently well.
  • a flexible membrane having a thickness of around 1 mm or less will be used.
  • the film is placed on the microtitre plate and the heated block is contacted with the film, the flexible membrane contacting the film.
  • the flexible membrane deforms to the shape of the apertured surface of the microtitre plate, the liquid flowing within the liquid cavity behind the flexible membrane.
  • the liquid cavity improves moulding of the shape of the substrate block with liquid cavity to the apertured surface of the microtitre plate, by providing a very soft deformable surface to engage with the film on the microtitre plate.
  • the liquid cavity also improves transfer of heat from the heating means to the film via the heated block.
  • the substrate block 214 with liquid filled cavity can be mounted beneath a heater block (not shown in figures 5 or 6), which heats the substrate block.
  • heating means may be located within the liquid filled cavity.
  • pressure can be applied between the soft block and the microtitre plate by means of suitable mechanisms within the apparatus or pressure could be applied manually by a user.
  • the apparatus may have suitable mechanics for moving the composite block towards and away from the microtitre plate to be sealed, while the microtitre plate is stationary.
  • the apparatus may have suitable mechanics for moving the microtitre plate towards or away from the composite block while the composite block is stationary.
  • the present application shows that the use of a heater block that is resiliently deformable, and therefore compressible / malleable, gives great improvements in thermal sealing.
  • the ability of a soft block to conform to the shape of the plate and any imperfections in its flatness allows sealing to become much more robust.
  • a further improvement because of this is the ability to seal 1536 well plates reliably.

Abstract

Apparatus for sealing a micro well plate (15) having a plurality of wells (15a), each well having an aperture in a surface of the micro well plate, the apparatus comprising a heat block (12), at least a portion of the heat block being resiliently deformable, wherein said at least a portion of the heat block is contactable in use with a film (16) to be sealed to the micro well plate to seal the plurality of apertures, the apparatus further comprising heating means for heating the heat block in use to seal the film to the micro well plate by melt-sealing the film to the micro well plate.

Description

Improvements to Microplate Sealing
FIELD OF THE INVENTION
This invention relates to improvements for sealing microplates used for scientific purposes, and more particularly, improvements relating to apparatus for sealing microplates and methods for sealing microplates.
BACKGROUND OF THE INVENTION
The science industry is an area of intense and fast moving research and development. Microtitre plates are typically formed of moulded plastic material, and are rectangular in shape having an array of wells, each well having a circular aperture in the top surface of the plate. The use of the microtitre plate (also known as the microplate or micro well plate), traditionally based on an array of 8 x 12 wells (i.e. having 96 wells) in a footprint of approximately 80mm x 120mm has gained universal acceptance. More recently the need for cost containment and throughput increases has given rise to the creation of 384 well plates (based on a 16 x 24 array of wells), 1536 well plates (based on a 32 x 48 array of wells) and higher still densities. As the density has increased so has the difficulty of manufacture of these parts. In particular, as the higher density plates have been created by injection moulding as one piece or two piece over moulded parts, the difficulty to seal the plates has increased to the point whereby it is no longer possible to seal the plates to a level whereby a number of applications are still enabled (such as high density compound storage, elevated temperature high density High throughput screening assays, or High density Polymerase Chain reaction assays). It is necessary to have a strong and robust seal in order to carry out such applications.
As mentioned above, one use of micro well plates is to parallel process multiple small volumes of samples by performance of polymerase chain reaction (PCR).
During PCR the micro well plate is received on a heated sample block which heats and cools the wells from below, cycling between a low temperature and a high temperature (the maximum temperature typically being around 9O0C to 980C).
Without some sort of sealing device to seal the micro well plate, the samples may evaporate from the wells, therefore in some prior art thermal cycler a sealing lid is provided in the thermal cycler device. Such thermocyclers have means for clamping the sealing lid against the top surface of the micro well plate to seal the sealing lid against the micro well plate. Condensation of vapour inside the wells may be prevented by heating the sealing lid, to maintain it at substantially the same temperature as the sample block below the micro well plate, such that there is no temperature differential across the height of the wells of the micro well plate (this is sometimes referred to as 'heated-lid technology'). The seal provided is only temporary, the seal only being maintained whilst the thermocycler device applies a clamping force between the sealing lid and the micro well plate.
In other applications, micro well plates require a removable, semi-permanent seal. Such semi-permanent seals are required for applications wherein the seal needs to be maintained even after the micro well plate has been removed from sealing apparatus, for example for storage of liquids in micro well plates for high density compound storage. Semi-permanent seals may also be required for micro well plates used in high density high throughput screening assays. A type of semipermanent seal used in the prior art is heat-sealable film. These are applied to the micro well plates using thermal sealer apparatus. After removal of the micro well plate from the thermal sealer apparatus, the seal provided by the heat-sealable film is maintained until a user peels off or punctures the sealing film.
To date a number of commercially available thermal sealers are available. These are available from Thermo Abgene (Epsom, Surrey) as the ALPS® 300 and 3000 and from Agilent Velocity 11 (Menlo Park, California). These instruments for the most part satisfy the needs of the current microplate sealing market. There are however a number of disadvantages where these instruments are not well suited. For example, the currently available thermal sealers are notably not suitable for sealing in cases when the plate density increases to above 384 wells per plate (i.e. these thermal sealers are not suitable for sealing 1536 well plates) and when the injection moulded plates have inconsistently moulded wells. By inconsistently moulded wells we mean where the injection mould has not filled perfectly or where there is wear in the mould tool, resulting in a non-flat top sealing surface of the plate.
The current thermal sealer instruments rely on the ability of the combination of pressure and heat to seal, thus minimising the effect of badly moulded plates. The principles of the process is to apply a seal normally made of a laminate of two differing melting point polymers to a plate and then to apply, either manually or in an automated fashion, heat via a preheated flat plate made of either copper or aluminium. The lower melting point polymer then melts with the top of the plate being sealed thus creating a bond and a seal. In some cases thermal glue is also incorporated into the seal itself. This process is not however able to deal with all badly moulded plates. Furthermore, 1536 well plates have such small wells that the combination of heat and pressure melts the plastic to the point that the wells are closed or badly mis-shaped. Damage to the plates reduces the number of times that a plate can be re-used. An improvement to this has been demonstrated by the use of Transmission laser welding in the patent GB 2 369 086, however this relies on the absorbance of the 808nm laser by a black surface. In the majority of cases a black surface is not available on the plate as clear is preferable for optical purposes.
SUMMARY OF THE INVENTION
According to the invention there is provided apparatus for sealing a micro well plate having a plurality of wells, each well having an aperture in a surface of the micro well plate, the apparatus comprising a heat block, at least a portion of the heat block being resiliently deformable, wherein said at least a portion of the heat block is contactable in use with a film to be sealed to the micro well plate to seal the plurality of apertures, the apparatus further comprising heating means for heating the heat block in use to seal the film to the micro well plate by melt-sealing the film to the micro well plate.
The heat block is resiliently deformable, such that it can conform to the top surface of a micro well plate to be sealed. It can be used to seal a film onto a micro well plate, the micro well plate having a plurality of apertures in its top surface. If the top surface of the micro well plate is not flat, the resiliently deformable heat block will conform to the top surface of the micro well plate, allowing the film to fully contact the top surface of the micro well plate and to form a strong, robust seal with the micro well plate. The apparatus therefore provides improved sealing over prior art thermal sealers. The entire heat block may be resiliently deformable, or alternatively a portion of the heat block may be deformable.
The film attaches to a surface of the micro well plate, around each aperture, by melting of the film or a portion of the film to the surface of the micro well plate. The heat block is heatable to a sufficiently high temperature by the heating means in order to melt the film onto the micro well plate. The apparatus is used to provide a removable, semi-permanent seal wherein the film remains sealed to the micro well plate, after removal of the micro well plate from the apparatus, until the seal is physically removed or broken by a user or by de-sealing apparatus. The film thus remains sealed to the micro well plate even after the heat source has been removed from the film (i.e. after the heat block has been moved away from the film).
Preferably the resiliently deformable heat block or heat block portion is contacted with the film for of the order of a few seconds or less in order to seal the film to the micro well plate. Preferably said at least a portion of the heat block is contacted with the film for less than 5 seconds, preferably less than 3 seconds, or preferably around 1 second or less.
There are examples of thermal cyclers in the prior art which use heated lid technology to seal micro well plates while they are in the thermal cycler, undergoing thermal cycling. EP 1 045 038 describes a thermo cycler which uses heated lid technology and has a high pressure heated lid comprising a screw mechanism, a heated rigid metal plate and an elastic insulating gasket which serves for tight pressuring of a polypropylene sealing film to the top surface of the multi well plate in the thermal cycler. The heated lid seals the wells during thermocycling and heating of the lid prevents condensation of vapour on the inside of the lid. The heated lid would only be heated up to around 100°C (so as not to heat the micro well plate contents above the maximum temperature needed for the PCR process) which is well below the melting temperature of the polypropylene film. In contrast to the present invention, the polypropylene film of the prior art heated lid technology used in the thermal cycler of EP 1 045 038 is temporarily forced tightly against the top surface of the micro well plate during thermal cycling and only seals the plate whilst pressure is applied between the film and the plate. In the thermal cycler of EP 1 045 038, the film is not melt-sealed to the micro well plate. In such prior art thermal cyclers, the seal is only maintained whilst screw mechanism holds the lid against the micro well plate.
Preferably said resiliently deformable heat block or heat block portion is made from a material selected from a group comprising silicon rubber, carbon enriched silicon rubber, fluoroelastomer, Viton ®, Alfas ® FEPM, Dyneon ®, FPM/FKM, PTFE and Tecnoflon ®. Preferably the resiliently deformable heat block or heat block portion comprises a resiliently deformable material incorporating a substance that increases the overall thermal conductivity of the resiliently deformable heat block or heat block portion. The substance increases the overall ability of the resiliently deformable heat block or heat block portion to transfer heat.
Preferably the resiliently deformable heat block or heat block portion comprises a resiliently deformable material incorporating a material of higher thermal conductivity than the resiliently deformable material. The resiliently deformable material may be impregnated throughout with material of high thermal conductivity such as a heat- conducting additive, or the resiliently deformable material may have material of high thermal conductivity embedded therein. This helps allow the heat block or heat block portion to reach the temperature necessary to melt the film to the micro well plate. Increasing the overall thermal conductivity of the heat block or heat block portion increases the temperature that it can be heated to, allowing the apparatus to melt the film by applying a high temperature to the film over a short time.
Preferably the resiliently deformable heat block or heat block portion comprises a resiliently deformable material enriched with a substance having a higher thermal conductivity than the resiliently deformable material. Preferably the resiliently deformable heat block or heat block portion comprises a resiliently deformable material enriched with metal powder. Preferably the resiliently deformable heat block or heat block portion is made from a material enriched with aluminium powder, copper powder, gold powder, silver powder, nickel powder or graphite powder.
Preferably the resiliently deformable heat block or heat block portion comprises a resiliently deformable material having a material of higher thermal conductivity than the resiliently deformable material embedded therein. Preferably the resiliently deformable heat block or heat block portion has at least one metal strip or metal wire embedded therein. Preferably the resiliently deformable heat block or heat block portion has a plurality of metal wires embedded therein, each metal wire being oriented with its axis perpendicular to the planar face of the resiliently deformable heat block or heat block portion that faces the micro well plate during sealing. The perpendicularly oriented wires improve conductance of heat to the film. Preferably the heat block includes a cavity therein, the cavity containing a fluid in use. Preferably the heat block includes a flexible membrane adjacent said cavity, such that during sealing of a micro well plate the fluid can flow within the cavity, the flexible membrane conforming to irregularities in the top surface of the micro well plate. The fluid flows within the cavity in response to pressure exerted on it through the flexible membrane, improving moulding of the shape of the heat block to the apertured surface of the micro well plate. The fluid within the heat block improves the overall heat transfer properties of the heat block, increasing the temperature that the heat block and film can be heated to. Preferably the fluid is oil, and more preferably the fluid is silicone oil. Preferably the boiling point of the fluid is above the temperature required to melt the film. Preferably the boiling point of the fluid is 12O0C or above. Preferably the boiling point of the fluid is 15O0C or above, or 16O0C or above. The heating means for heating the heat block may be located within the fluid filled cavity or alternatively external to the fluid filled cavity but in thermal contact with the fluid filled cavity.
Preferably the resiliently deformable heat block or heat block portion is heatable to a temperature sufficient to seal the film to the micro well plate by melt-sealing the film to the micro well plate. The resiliently deformable heat block or heat block portion has an overall thermal conductivity such that it is heatable to a temperature sufficient to seal the film to the micro well plate by melt-sealing the film to the micro well plate. Preferably said resiliently deformable heat block or heat block portion is heatable to at least 1200C. In other words, the temperature of the heat block or heat block portion can reach at least 1200C in use during sealing. Preferably said resiliently deformable heat block or heat block portion is heatable to at least 150°C. Preferably said resiliently deformable heat block or heat block portion is heatable to at least 1600C.
Preferably said resiliently deformable heat block or heat block portion is made of a material with a Shore hardness on the A scale of between 10 and 100 inclusive, or more preferably, of between 30 and 50 inclusive.
Preferably the resiliently deformable heat block is capable of withstanding a temperature of up to at least 150°C, but more preferably 200°C, and most preferably 2500C. Preferably the heating means for heating the heat block are located, in use, within the deformable heat block or heat block portion.
Alternatively the apparatus further comprises a heat plate, wherein the heat plate is heated in use and contacts said resiliently deformable heat block or heat block portion during sealing of a micro well plate. The heat plate may be a rigid heat plate. Preferably said resiliently deformable heat block or heat block portion is attached to the heat plate in use.
Preferably the heat plate comprises a vacuum plate. Suitably, the vacuum plate has a plurality of through holes, the through holes being in communication with a suction pump, the resiliently deformable heat block or heat block portion having a plurality of through holes. This enables the heat block to be used to pick up the film and place it on top surface of the micro well plate, via the vacuum force applied through the holes in the vacuum plate and the heat block or heat block portion. Preferably the vacuum plate comprises a copper vacuum plate.
Preferably the means for heating the heat block or heat block portion comprises a resistive heater.
Preferably the apparatus further comprises means for moving the heat block or heat block portion up and down, in use, relative to a micro well plate. The moving device can move the heat block or heat block portion towards or away from the micro well plate in use. Alternatively, the apparatus further comprises means for moving a micro well plate up and down, in use, relative to the heat block or heat block portion. The moving device can move the micro well plate towards or away from the heat block or heat block portion in use.
Preferably the apparatus further comprises force applying means for applying a force between the heat block and a micro well plate.
Preferably the heat block or heat block portion is heated, in use, via heat conduction. Particularly preferably, the heat block or heat block portion is heated by contacting it, in use, with a heated body or plate. According to another aspect of the invention there is provided a method of sealing a micro well plate having a plurality of wells, each well having an aperture in a top surface of the micro well plate, the method comprising the steps of:
(i) providing apparatus for sealing a micro well plate, the apparatus comprising a heat block, at least a portion of the heat block being resiliently deformable, the apparatus further comprising heating means for heating the heat block in use,
(ii) placing a film on the top surface of the micro well plate, and (iii) contacting the heated, resiliently deformable heat block or heat block portion with the film, to seal the plurality of apertures by melt-sealing the film to the micro well plate.
Preferably the heat block is heated by heating means located within the heat block.
Alternatively the heat block is heated by a rigid heat plate, the heat plate being heated by heating means. The heating means for heating the rigid heat plate may be located within the heat plate or adjacent the heat plate in use. Suitably the heat block is attached to the underside, in use, of the rigid heat plate. In this way, the heat block is heated by the heat plate, and the resiliently deformable heat block or heat block portion can be brought into contact with the film to be sealed to the micro well plate. Alternatively, after step (ii), the resiliently deformable heat block or heat block portion is placed on a top surface of the film and the heated rigid heat plate is contacted with the heat block, to heat the heat block.
Preferably the method further comprises the step of applying a force between the heat block and the micro well plate. Preferably, the film comprises a polymer film or foil which is sealable to a micro well plate when heated.
Preferably the rigid heat plate comprises a vacuum plate, the vacuum plate having a plurality of through holes, the plurality of through holes being in communication with a suction pump, the resiliently deformable heat block comprising a plurality of through holes, wherein in step (ii) the resiliently deformable heat block is used to pick up the film using suction force and to place the film on the top surface of the micro well plate. BRIEF DESCRIPTION OF THE DRAWINGS
The invention will now be described, by way of example only, with reference to the accompanying drawings in which:-
Figure 1 shows a perspective view of a composite soft block for use in an embodiment of the invention;
Figure 2A-2D show schematic diagrams depicting sealing of a microtitre plate using prior art thermal sealers and using a soft heat block according to the present invention; figure 2A shows a well-moulded microtitre plate being sealed in a conventional manner using a prior art thermal sealer; figure 2B shows a badly moulded plate being sealed in a conventional manner using a prior art thermal sealer; figure 2C shows a badly moulded plate prior to application of a soft block / heater block to seal the microtitre plate; figure 2D shows a badly moulded plate being sealed with a soft block / heater assembly;
Figure 3 shows a perspective view of a substrate block part of a composite block according to another embodiment of the invention;
Figure 4 shows a perspective view of the substrate block of figure 3 with a soft block attached to it;
Figure 5 shows a perspective view of a substrate block of a composite block with a liquid filled cavity according to a further embodiment of the invention;
Figure 6 shows a perspective view of the substrate block of figure 5 having a flexible membrane placed on it;
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Figure 2C shows a schematic diagram of a badly moulded microtitre plate 15 being sealed with a film 16 using a prior art thermal sealer 20. Figure 2C demonstrates the problems of such prior art sealers. The thermal sealer 20 has a heated metal flat plate 21. If the microtitre plate 15 is badly moulded, and has a non-flat top surface as shown in figure 2C, a sealing film 16 cannot be reliably sealed to the top surface of the plate, as in some places, the film does not contact the top surface of the plate during the sealing operation. Because of the uneven surface of the badly moulded microtitre plate 15, a reliable seal cannot be formed between the film 16 and the microtitre plate 15.
Embodiments of the present invention are described below by way of example only. These examples represent the best ways of putting the invention into practice that are currently known to the applicant although they are not the only ways in which this could be achieved.
Referring to figure 1 , this shows a composite block 10 for use in apparatus for sealing micro well plates according to an embodiment of the invention. The composite block 10 comprises a soft block 1 1 of material that is attached to a thermally conducting heater block 12. The soft block 1 1 is made of a material that is resiliently deformable, is able to conduct heat, and that is able to withstand high temperatures that are required in sealing microtitre plates. The resiliently deformable soft block 1 1 may be made of a number of suitable materials, including silicon rubber, carbon enriched silicon rubber, Viton ®, Alfas ® FEPM, Dyneon ®, fluoroelastomers (also known as FPM/FKM), nitrile, PTFE or Tecnoflon ®. Preferably the soft block 11 is made of a soft material, having a shore hardness measured on the A scale of between 10-100 inclusive and capable of withstanding up to at least 1500C, but more preferably 2000C and most preferably 250°C in temperature.
The resiliently deformable material may be enriched with an additive of high thermal conductivity, such as a metal powder, for example aluminium, copper, gold, silver or nickel powder. Alternatively the resiliently deformable material may be enriched with graphite powder.
Alternatively, or in addition, the thermal conductivity of the soft block can be increased by embedding metal wire or metal strips within the resiliently deformable material.
The soft block 11 is attached to the underside of a heater block 12. Between the soft block 11 and the heater block 12 is a soft block substrate plate 14, which is a plate typically made of aluminium or copper on which the soft block 1 1 is formed during manufacture of the soft block 1 1. The soft block substrate 14 on which the soft block 1 1 has been formed is mounted to the heater block 12 in order to mount the soft block 1 1 to the heater block 12. The heater block 12 is thermally conducting and is heated using one or more resistive heaters. Preferably four 125 Watt cartridge heaters or one or more silicone flat elements are used to heat the heater block 12. The heater block 12 is attached to a thermally insulated block 13, which stops heat transferring away from the heater block 12 and soft block 11 , and away from the film and microtitre plate to be sealed.
The apparatus may include a support (not shown), , such as a rotary plate support, for holding/supporting the microtitre plate to be sealed whilst pressure is applied between the composite block 10 and the microtitre plate.
Referring to figures 2C and 2D, schematic diagrams showing sealing of a microtitre well plate 15 using a composite block 10 of the present invention are shown. The microtitre plate 15 has a plurality of wells 15a. In order to seal a microtitre plate 15, a planar seal or film 16 is placed over the apertures of a microtitre plate. The heated composite block 1 1 is then brought into contact with the film 16 and pressure is applied between the soft block 11 and the microtitre plate 15. The soft block 11 on the underside of the heater block 12 is resiliently deformable, and therefore deforms, conforming to the shape of the top surface of the plate 15, as shown in figure 2D. Therefore, if sealing a badly moulded plate 15, in which the top surface of the plate is not flat, the soft block 11 conforms to the shape of the top surface of the plate 15, enabling a strong seal to be formed between the film 16 and the top surface of the plate 15.
The use of a resiliently deformable soft block 11 to contact the film 16 gives superior performance to a rigid heater block (schematic diagrams showing sealing using prior art thermal sealers are shown in figures 2A and 2B). The soft block 11 is able to conform to the shape of the plate 15, such that the plate can be reliably sealed despite having imperfections in its surface flatness. A further advantage of the present invention is that it allows reliable sealing of 1536 well plates, as 1536 well plates could not be reliably sealed using prior art sealing apparatus. Well plates typically have a total area of around 80-85 mm by 120-125 mm. Each well in a 1536 well plate typically has an aperture diameter in the surface of the plate of around 1.7 mm. The surface of the soft block 1 1 which engages with the film in use during sealing is preferably rectangular in shape and is a solid rectangular or substantially solid rectangular surface, with no or substantially no voids. Preferably the surface of the soft block 11 that engages with the film in use is at least 85 x 125 mm in size, therefore it covers the whole of the well plate, covering each well aperture in the surface of the well plate. Of course, 384 and 96 well plates can be sealed using this apparatus. 384 well plates have wells having an aperture diameter of around 3.6 mm and 98 well plates have wells having an aperture diameter of around 4.8-5 mm. The apparatus of the present invention is therefore suitable for sealing plates having a plurality of apertures, each aperture having a diameter of less than 10 mm, and preferably less than 5 mm.
A further advantage of the present invention is that any solvent or reagents that have been spilled on the top surface of the microtitre plate 15 will be forced off the top surface of the plate 15 whilst pressure is applied between the soft block 1 1 and the plate 15. When using prior art thermal sealers as shown in figure 2B, any solvent or reagents spilled on the top surface of the plate 15 would be trapped between the top surface of the plate 15 and the film 16; when the heated flat plate 21 is applied, the solvent or reagent would be heated, causing it to boil and form bubbles between the top surface of the plate 15 and the film 16, thus creating areas where the film 16 is not fully sealed to the plate 15. The use of the soft block 11 of the present invention overcomes this problem by forcing the spilled liquid off the top surface of the plate 15.
The film 16 may be any film used in conventional thermal sealers. For example, the film may be a planar seal made of a laminate of two differing melting point polymers or a foil / polymer laminate.
The soft block 1 1 need not be formed on a substrate plate 14, in which case a resiliently deformable soft block 1 1 could be mounted directly onto a heater block 12.
Alternatively, instead of using a composite block wherein a soft block is mounted to the underside of a rigid heater block, a soft block which is separate from a rigid heater block may be used. The soft block may be placed on top of a microtitre plate on which a film has been located. Heater means, such as a rigid heater block may then be brought into contact with the soft block 11 to seal the film to the microtitre plate. Therefore, the soft block need not be mounted to a rigid heater block, but may comprise a separate part of the apparatus, which is brought into contact with the rigid heater block during sealing in order to heat the soft block.
In an alternative embodiment, the heater block 12 may be a copper vacuum plate. This aids heat transfer to the front of the soft block 1 1. The copper vacuum plate has one or more through holes which lead to a vacuum chamber comprising a vacuum or suction pump. The soft block also comprises one or more through holes. When the suction pump is in use, this provides a vacuum force enabling the film to be picked up using the soft block and to be placed on the top surface of the microtitre plate. An advantage of using a copper vacuum plate is therefore that a suction force can be created which can be used to pick the film up and transfer it to the top of the micro well plate to be sealed. This system is more reliable in picking up and transferring the sealing film than prior art systems.
In a further alternative embodiment, instead of heating the soft block 1 1 using a heater contained within a rigid heater block, there may be heating means, such as one or more resistive heaters, embedded in the soft block 11 for heating the soft block. The soft block may be attached to means for applying a force between the soft block and the microtitre plate. Alternatively an individual, separate soft block with embedded heating means may be placed on top of a film, which has been placed on the top surface of a microtitre plate, and the apparatus may apply force between the heated soft block and the microtitre plate to seal the microtitre plate.
Referring to figures 3 and 4, in another embodiment, a Teflon covered aluminium or copper platen is provided as a substrate block 1 14. Referring to figure 3, a layer of thermally conductive closed cell silicone sponge rubber, such as ThermacoolR™ R-
10404 from Saint-Gobain is glued to the underside of the substrate block 1 14 (the underside of the substrate block 1 14, which faces the apertured surface of the microtitre plate in use, is shown uppermost in figures 3 and 4). The layer of silicone sponge rubber acts as a soft block 1 11 , similar to the soft block 1 1 of figure 1. The thermal conductivity of the closed cell silicone sponge rubber increases with compression of the material, the material having a thermal conductivity of 0.65
W/mK at 50% compression. The layer of closed cell silicone sponge rubber 11 1 is glued to the substrate block 1 14 using a thermally conductive adhesive; for example, a thermally conductive acrylic transfer adhesive may be used as the adhesive, allowing heat to transfer from the substrate block to the soft block 1 11. Similarly to the embodiment of figure 1 , in the thermal sealer apparatus the substrate block 1 14 would be connected below a heater block (not shown in figures 3 or 4), the heater block containing heater elements. The heater block would be connected underneath an insulating block (not shown in figures 3 or 4), which insulates the mechanics of the thermal sealer apparatus from the heat generated by the heater block. The substrate block 1 14 has four suction cups or vacuum cups 130, one at each corner of the rectangular face of the substrate block 1 14 which faces towards the apertured surface of the microtitre plate in use. The vacuum cups 130 link with vacuum flow channels incorporated in the substrate block 114 and heater block, which lead to a vacuum or suction pump, which provides a vacuum force enabling the film to be picked up using the substrate block 1 14 and placed on the top surface of the microtitre plate.
As referred to above, the thermal conductivity of the resiliently deformable material can be increased by embedding metal wire or metal strips within the resiliently deformable material. For example, instead of gluing a closed cell silicone rubber layer 11 1 to the substrate block 114 of figure 4, a layer of silicone rubber having monel or aluminium metal wires embedded therein can be glued to the substrate block using a thermally conductive adhesive, such as thermally conductive acrylic transfer adhesive. Preferably, the wires are orientated perpendicular to the planar surface of the silicone rubber block which contacts the sealing film in use. A suitable material, having 900 wires per square inch of silicone rubber oriented perpendicular to the rubber planar face, is available from Kemtron Ltd, Essex UK. During sealing, the ends of the wires in the silicone rubber contact both the metal substrate block and the sealing film, assisting transfer of heat from the heater block to the sealing film, whilst providing a soft block which deforms to the surface of the microtitre plate. Of course, wires of metals other than monel or aluminium may be used to embed the soft block.
Referring to figures 5 and 6, in a further alternative embodiment, the heated block contains a liquid filled cavity. Similar to the embodiment of figures 3 and 4, the composite block includes a Teflon covered aluminium or copper platen or substrate block 214. The substrate block 214 is machined to produce a cavity 240 having four side walls 241. Preferably a cavity having a depth of around 5 mm is machined in the substrate block 214. The cavity 240 is filled with a liquid 242, such as a silicone based oil. For example, a phenyl methyl silicone oil called 702 Silicone Oil may be used. Referring to figure 6, a flexible membrane 243 is placed across the opening of the cavity 240 and sealed to the side walls 241 of the cavity 240. A suitable material for the flexible membrane is ThermacoolR™ TC3006 from Saint-Gobain, which is a very soft ceramic-filled silicone elastomer, having a thermal conductivity of around 1.1 VWmK. Preferably the flexible membrane is thick enough such that it is durable, and not liable to be punctured, but is thin enough such that it transfers heat to the sealing film sufficiently well. Preferably a flexible membrane having a thickness of around 1 mm or less will be used.
Instead of a silicone oil, mineral oil, water, or other liquids could be used to fill the cavity. Preferably the boiling point of the liquid is above the temperature to which the heated block needs to be heated in order to melt the film. During use, the film is placed on the microtitre plate and the heated block is contacted with the film, the flexible membrane contacting the film. The flexible membrane deforms to the shape of the apertured surface of the microtitre plate, the liquid flowing within the liquid cavity behind the flexible membrane. The liquid cavity improves moulding of the shape of the substrate block with liquid cavity to the apertured surface of the microtitre plate, by providing a very soft deformable surface to engage with the film on the microtitre plate. The liquid cavity also improves transfer of heat from the heating means to the film via the heated block. Similar to the embodiment of figure 1 , the substrate block 214 with liquid filled cavity can be mounted beneath a heater block (not shown in figures 5 or 6), which heats the substrate block. Alternatively, heating means may be located within the liquid filled cavity.
In all of the above embodiments, pressure can be applied between the soft block and the microtitre plate by means of suitable mechanisms within the apparatus or pressure could be applied manually by a user. In all of the above embodiments, the apparatus may have suitable mechanics for moving the composite block towards and away from the microtitre plate to be sealed, while the microtitre plate is stationary. Alternatively, the apparatus may have suitable mechanics for moving the microtitre plate towards or away from the composite block while the composite block is stationary.
In summary, the present application shows that the use of a heater block that is resiliently deformable, and therefore compressible / malleable, gives great improvements in thermal sealing. The ability of a soft block to conform to the shape of the plate and any imperfections in its flatness allows sealing to become much more robust. A further improvement because of this is the ability to seal 1536 well plates reliably.

Claims

Claims
1. Apparatus for sealing a micro well plate having a plurality of wells, each well having an aperture in a surface of the micro well plate, the apparatus comprising a heat block, at least a portion of the heat block being resiliently deformable, wherein said at least a portion of the heat block is contactable in use with a film to be sealed to the micro well plate to seal the plurality of apertures, the apparatus further comprising heating means for heating the heat block in use to seal the film to the micro well plate by melt-sealing the film to the micro well plate.
2. Apparatus according to claim 1 wherein said resiliently deformable heat block or heat block portion is made from a material selected from a group comprising silicon rubber, carbon enriched silicon rubber, fluoroelastomer, Viton ®, Alfas ® FEPM, Dyneon ®, FPM/FKM, PTFE and Tecnoflon ®.
3. Apparatus according to any preceding claim, wherein the resiliently deformable heat block or heat block portion comprises a resiliently deformable material incorporating a substance that increases the overall thermal conductivity of the resiliently deformable heat block or heat block portion.
4. Apparatus according to any preceding claim, wherein the resiliently deformable heat block or heat block portion comprises a resiliently deformable material incorporating a material of higher thermal conductivity than the resiliently deformable material.
5. Apparatus according to any preceding claim, wherein the resiliently deformable heat block or heat block portion comprises a resiliently deformable material enriched with a substance having a higher thermal conductivity than the resiliently deformable material.
6. Apparatus according to any preceding claim, wherein the resiliently deformable heat block or heat block portion comprises a resiliently deformable material enriched with metal powder.
7. Apparatus according to any preceding claim, wherein the resiliently deformable heat block or heat block portion is made from a material enriched with aluminium powder, copper powder, gold powder, silver powder, nickel powder or graphite powder.
8. Apparatus according to any preceding claim, wherein the resiliently deformable heat block or heat block portion comprises a resiliently deformable material having a material of higher thermal conductivity than the resiliently deformable material embedded therein.
9. Apparatus according to claim 8, wherein the wherein the resiliently deformable heat block or heat block portion has at least one metal strip or metal wire embedded therein.
10. Apparatus according to any preceding claim, wherein the heat block includes a cavity therein, the cavity containing a fluid in use.
1 1. Apparatus according to claim 10, wherein the heat block includes a flexible membrane adjacent said cavity, such that during sealing of a micro well plate the fluid can flow within the cavity, the flexible membrane conforming to irregularities in the top surface of the micro well plate.
12. Apparatus according to any preceding claim, wherein said resiliently deformable heat block or heat block portion is heatable to a temperature sufficient to seal the film to the micro well plate by melt-sealing the film to the micro well plate.
13. Apparatus according to any preceding claim, wherein said resiliently deformable heat block or heat block portion is heatable to at least 1200C.
14. Apparatus according to any preceding claim, wherein said resiliently deformable heat block or heat block portion is heatable to at least 1500C.
15. Apparatus according to any preceding claim, wherein said resiliently deformable heat block or heat block portion is heatable to at least 1600C.
16. Apparatus according to any preceding claim wherein said resiliently deformable heat block or heat block portion is made of a material with a Shore hardness on the A scale of between 10 and 100 inclusive.
17. Apparatus according to any preceding claim wherein said resiliency deformable heat block or heat block portion is made of a material with a Shore hardness on the A scale of between 30 and 50 inclusive.
18. Apparatus according to any preceding claim wherein said resiliently deformable heat block is capable of withstanding a temperature of up to at least 1500C.
19. Apparatus according to any preceding claim wherein said resiliently deformable heat block is capable of withstanding a temperature of up to at least 2000C.
20. Apparatus according to any preceding claim wherein said resiliently deformable heat block is capable of withstanding a temperature of up to at least
250°C.
21. Apparatus according to any preceding claim wherein the heating means for heating the heat block are located, in use, within the deformable heat block or heat block portion.
22. Apparatus according to any preceding claim, the apparatus further comprising a heat plate, wherein the heat plate is heated in use and contacts said resiliently deformable heat block or heat block portion during sealing of a micro well plate.
23. Apparatus according to claim 22 wherein the heat plate is a rigid heat plate.
24. Apparatus according to either of claims 22 or 23 wherein said resiliently deformable heat block or heat block portion is attached to the heat plate in use.
25. Apparatus according to any of claims 22 to 24 wherein the heat plate comprises a vacuum plate.
26. Apparatus according to claim 25 wherein the vacuum plate has a plurality of through holes, the through holes being in communication with a suction pump, the resiliently deformable heat block or heat block portion having a plurality of through holes.
27. Apparatus according to claim 25 or 26 wherein the vacuum plate comprises a copper vacuum plate.
28. Apparatus according to any preceding claim, the means for heating the heat block or heat block portion comprising a resistive heater.
29. Apparatus according to any preceding claim, the apparatus further comprising means for moving the heat block or heat block portion up and down, in use, relative to a micro well plate.
30. Apparatus according to any preceding claim, the apparatus further comprising means for moving a micro well plate up and down, in use, relative to the heat block or heat block portion.
31. Apparatus according to any preceding claim, the apparatus further comprising force applying means for applying a force between the heat block and a micro well plate.
32. Apparatus according to any preceding claim wherein the heat block or heat block portion is heated, in use, via heat conduction.
33. Apparatus according to any preceding claim wherein the heat block or heat block portion is heated by contacting it, in use, with a heated body or plate.
34. A method of sealing a micro well plate having a plurality of wells, each well having an aperture in a top surface of the micro well plate, the method comprising the steps of:
(i) providing apparatus for sealing a micro well plate, the apparatus comprising a heat block, at least a portion of the heat block being resiliently deformable, the apparatus further comprising heating means for heating the heat block in use, (ii) placing a film on the top surface of the micro well plate, and (iii) contacting the heated, resiliently deformable heat block or heat block portion with the film, to seal the plurality of apertures by melt-sealing the film to the micro well plate.
35. A method of sealing a micro well plate according to claim 34 wherein the heat block is heated by heating means located within the heat block.
36. A method of sealing a micro well plate according to claim 34 or 35 wherein the heat block is heated by a rigid heat plate, the heat plate being heated by heating means.
37. A method of sealing a micro well plate according to claim 36 wherein the heat block is attached to the underside, in use, of the rigid heat plate.
38. A method of sealing a micro well plate according to claim 36 wherein after step (ii), the resiliently deformable heat block or heat block portion is placed on a top surface of the film and the heated rigid heat plate is contacted with the heat block, to heat the heat block.
39. A method of sealing a micro well plate according to any of claims 34 to 38 wherein the method further comprises the step of applying a force between the heat block and the micro well plate.
40. A method of sealing a micro well plate according to any of claims 34 to 39 wherein the film comprises a polymer film or foil which is sealable to a micro well plate when heated.
41. A method of sealing a micro well plate according to any of claims 34 to 40 wherein the rigid heat plate comprises a vacuum plate, the vacuum plate having a plurality of through holes, the plurality of through holes being in communication with a suction pump, the resiliently deformable heat block comprising a plurality of through holes, wherein in step (ii) the resiliently deformable heat block is used to pick up the film using suction force and to place the film on the top surface of the micro well plate.
42. A method of sealing a micro well plate using the apparatus of any of claims 1 to 33.
43. Apparatus for sealing a micro well plate and a method of sealing a micro well plate substantially as herein described with reference to and as illustrated in any combination of the accompanying drawings.
PCT/GB2009/050753 2008-06-27 2009-06-29 Improvements to microplate sealing WO2009156767A2 (en)

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WO2009156767A3 (en) 2010-05-27
GB2461182A (en) 2009-12-30
GB0911162D0 (en) 2009-08-12

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