WO2002072423A1 - Couvercle de microplaque - Google Patents

Couvercle de microplaque

Info

Publication number
WO2002072423A1
WO2002072423A1 PCT/US2002/006942 US0206942W WO02072423A1 WO 2002072423 A1 WO2002072423 A1 WO 2002072423A1 US 0206942 W US0206942 W US 0206942W WO 02072423 A1 WO02072423 A1 WO 02072423A1
Authority
WO
WIPO (PCT)
Prior art keywords
microplate
lid
channel
fluid
interface
Prior art date
Application number
PCT/US2002/006942
Other languages
English (en)
Inventor
Michael Mcneely
Nils Adey
Original Assignee
Biomicro Systems, Inc.
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 Biomicro Systems, Inc. filed Critical Biomicro Systems, Inc.
Publication of WO2002072423A1 publication Critical patent/WO2002072423A1/fr

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—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
    • B01L3/502715—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 interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • 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
    • B01L3/0203—Burettes, i.e. for withdrawing and redistributing liquids through different conduits
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
    • B01L3/5085—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
    • B01L3/50853—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates with covers or lids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00279—Features relating to reactor vessels
    • B01J2219/00306—Reactor vessels in a multiple arrangement
    • B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
    • B01J2219/00315—Microtiter plates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00279—Features relating to reactor vessels
    • B01J2219/00331—Details of the reactor vessels
    • B01J2219/00333—Closures attached to the reactor vessels
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00351—Means for dispensing and evacuation of reagents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0642—Filling fluids into wells by specific techniques
    • 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
    • B01L2300/04—Closures and closing means
    • B01L2300/046—Function or devices integrated in the closure
    • 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
    • B01L2300/04—Closures and closing means
    • B01L2300/046—Function or devices integrated in the closure
    • B01L2300/048—Function or devices integrated in the closure enabling gas exchange, e.g. vents
    • 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
    • B01L2300/04—Closures and closing means
    • B01L2300/046—Function or devices integrated in the closure
    • B01L2300/049—Valves integrated in closure
    • 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
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0864—Configuration of multiple channels and/or chambers in a single devices comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
    • 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
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0867—Multiple inlets and one sample wells, e.g. mixing, dilution
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—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
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B60/00—Apparatus specially adapted for use in combinatorial chemistry or with libraries
    • C40B60/14—Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries

Definitions

  • the present invention relates generally to the field of laboratory equipment, and particularly to multi-well microplates used to contain multiple fluid samples for chemical and biological reactions or processing steps. More specifically, the present invention relates to a novel lid for use with such microplates, which includes microfluidic circuitry to facilitate delivery of fluid to microplate wells, and which functions in combination with the microplate to provide additional or enhanced fluid processing. Description of Related Art
  • Microplates are common laboratory hardware used for numerous liquid based chemical and biological reactions.
  • the standard microplate, or microtiter plate contains 96 wells in an 8x12 row and column pattern, with the wells having 9 mm center-to-center spacing.
  • Microplates are also available with 384 wells and 1536 wells. The overall dimensions of the plates do not vary very much from type to type.
  • the well-to-well spacing may vary, but is always a multiple of the 9 mm of the standard microtiter plate, such as 4.5 mm for the 384 well plate, and 2.25 mm for the 1536 well plate.
  • a typical 96 well microplate is indicated by reference number 10 in FIG. 1.
  • microplates are made of various materials (typically rigid plastics) depending on their intended applications, and may have biological or chemical coatings suitable for the chemistries to be performed in them.
  • strips of wells that conform to the typical 9 mm well spacing of the microtiter plate, but that include only one column of (for example) 8 wells attached together, or two 8-well columns for a total of 16 wells, or sometimes one or more columns of 12 wells. These strips can also often fit in the various instruments designed for handling and processing microplates, which include heaters, optical plate readers, plate washers, and pipetting equipment, either manual or robotic.
  • Fluid is typically added to or removed from the wells of microplates using manual or automated pipettors. Lids are often placed on microplates to enclose the fluid within and minimize loss of fluid due to evaporation. Such lids are relatively simple structures, formed of rigid or flexible polymeric materials that fit over the microplate. Some form a tight seal with the microplate; some do not. It is also common to cover microplates with adhesive film to prevent evaporation or spilling of well contents.
  • a common laboratory task is to load liquid samples into the wells of a microtiter plate. This may be done by manually pipetting the samples into each well, or by using robotic pipetting systems to perform the task.
  • Manual and robotic pipetting devices typically have multiple pipette tips spaced at intervals compatible with standard well spacings. Such devices greatly facilitate the loading of samples and reagents into microplates. However, they are not particularly effective when it is necessary to load very small fluid volumes into microplate wells. It is usually extremely difficult to manually load very small volumes, such as 0.5 ⁇ l, into the microplate wells. It is also difficult for a robotic pipettor to load such small volumes repeatably and reliably onto a plate.
  • microplates are well-established and commonly used laboratory devices that are compatible with various types of other laboratory equipment, it would be desirable to provided enhanced function to microplates, such as improved sample and reagent fluid processing capability, while retaining the same basic format for compatibility with existing equipment.
  • This invention relates to the construction and use of a microfluidic interface microplate lid in which microfluidic structures are incorporated into a microplate lid to provide for the delivery of liquid to and removal of liquid from the wells of the microplate in finely regulated quantities.
  • Lids constructed according to the invention may also provide the functions of metering, mixing or dividing sample aliquots, perform complex distribution of fluid, allow for pressurization of reactions that take place in the wells of the microplate or within the lid itself, and numerous other functions.
  • the body of the inventive lid is thick enough to include various fluid processing, control, or sensing structures.
  • the lid further includes multiple projections on its underside, which fit into the microplate wells to seal the wells and provide controlled transport of fluid and gas to and from the wells.
  • the fluidic processing that takes place within the lid may be controlled by the use of passive fluid control technology or remote valving, as described in previously filed, commonly-owned U.S. Patent 6,296,020, issued October 2, 2001, and PCT International Patent Publication No. WO 02/12734 (which are incorporated herein by reference), or active control mechanisms, such as mechanical valves, electrokinetics, or any combination of these methods. Active sensing, e.g., of fluid location or temperature, may also take place. If the plate is to be heated, the well contents may be pressurized, through the lid, to reduce evaporation and prevent boiling. The general approach of controlling pressure in a reaction chamber has been described previously in Applicant's PCT International Patent Publication No.
  • the invention includes microfluidic interface microplate lids that fit either entire 96 well, 384 well, or 1536 well plates, single column or multiple column strips that comprise a portion of a microplate, or any other multiple or shape of fluid containment device used in liquid analysis.
  • the microfluidic interface microplate lid can take a fluid volume injected into it and aliquot it into the number of desired wells. Multiple samples can be injected, as desired, and the division of the samples need not be equal. One ⁇ l or less may be delivered, and the fluid will not evaporate because the well is covered and its exposure to air is controlled. There is no need for oil to be deposited to reduce evaporation.
  • microplate lid may be designed to extract liquid from a well and deliver it to an integrated microdetection system, such as a microelectrophoresis system, or, by removing the lid, the fluid in the well may be available for conventional extraction and transfer to another external system. Micro beads often used in some chemical processes could also be present and easily contained in a well. If fluidic processing requires thermal cycling, or incubation, the plate and lid may be placed in a microplate heater. The fixture holding the plate may be specialized to fit the lid, and may contain pumping and control mechanisms to run the fluidic processing.
  • Another object of the invention to allow the removal of small, finely controlled volumes of fluid from microplate wells. This is achieved by the inclusion of fluid-removal microchannels that projects into wells to remove fluid from the wells.
  • Another object of the invention is to regulate the venting of air from microplate wells. This is achieved by providing air vents that communicate with microplate wells in the microplate lid. It is further possible to apply a back pressure to the air vent in order to regulate pressure in the well to prevent boiling and/or reduce evaporation
  • a further objective of the invention is to modify the volume of wells in a microplate by providing a lid with protrusions that extend into and partially fill the wells, thereby reducing the available reaction volume. This has the advantage of reducing the air space into which evaporation of sample may occur.
  • Yet another object of the invention is to provide for the mixing of sample or reagent fluids with other fluids or solids prior or subsequent to delivery to microplate wells. This is accomplished through the use of microfluidic processing circuitry in the microplate lid. Mixing of fluids can be used advantageously to dilute samples or reagents or combine materials for various pre- or post-processing reactions.
  • a related object of the invention is to provide for incubation and reaction steps to be carried out in the microplate lid before or after delivery to microplate wells. This objective is accomplished by providing reaction wells within the microplate lid, and further by providing a mechanism for controlling reaction conditions within the wells to carry out the desired reaction. This has the advantage of making it possible to perform multiple reaction steps without moving fluid samples from the microplate to another device.
  • Yet another object of the invention is to provide a microplate lid which includes active elements such as mechanical valves, sensors, heating elements, and the like, in order to perform complex fluid handling and processing steps in a conventional microplate format.
  • FIG. 1 illustrates a typical 96-well microtiter plate and a microplate lid constructed according to the present invention
  • FIG. 2 is a close-up view of a single well-interface protrusion of a microplate lid constructed according to the present invention
  • FIG. 3 is a cross section of a three-layer well-interface protrusion positioned in a microplate well;
  • FIG. 4 is a cross section of a two-layer well-interface protrusion positioned in a microplate well
  • FIG. 5 is a perspective view of an interface layer of a microfluidic microplate lid showing channels leading into and out of a well-interface protrusion;
  • FIG. 6 is a perspective view of an protrusion of a microplate lid having channels for delivering fluid to and extracting fluid from a microplate well;
  • FIG. 7 is a cross-sectional view of the protrusion shown in FIG. 6;
  • FIG. 8 is an alternative embodiment of a protrusion for delivering fluid to and extracting fluid from a microplate well
  • FIG. 9 illustrates a microfluidic interface microplate lid covering two columns of a standard
  • FIG. 10 illustrates fluid traveling through a first well in a microplate prior to being divided and delivered to two other wells of the microplate
  • FIG. 11 illustrates fluid traveling through a well in the microplate lid prior to delivery to two wells of a microplate
  • FIG. 12 is a schematic representation of microfluidic circuitry for distributing fluid to sixteen wells of a microplate
  • FIG. 13 illustrates a microfluidic interface microplate lid which divides a single fluid stream and provides aliquots to sixteen wells of a microplate
  • FIG. 14 illustrates an alternative microfluidic interface microplate lid that divides a single fluid stream to provide aliquots to sixteen wells of a microplate.
  • FIG. 1 illustrates a standard 96-well microplate 10 and a microplate lid 12 constructed according to the present invention.
  • Microplate 10 is, for example, an injection molded plastic structure having a substantially planar upper surface 14 with a plurality of wells 16 disposed therein in a grid pattern.
  • Microplate lid 12 has a substantially planar base structure 18 with a plurality of well-interface protrusions 20 extending from a lower surface thereof.
  • Each well-interface protrusion includes a fluid inlet 17 and an outlet 19, which may provide for either air or liquid to exit the system.
  • Fluid inlet 18 may be connected to an external source of sample or reagent fluids.
  • Outlet 19 may be connected to equipment that will perform further processing of sample fluids or it may provide for the venting of air, or the pressurization of the system.
  • a single inlet 17 and outlet 19 are depicted, but certain embodiments of the inventive microplate lid may include larger numbers of either structure.
  • Well-interface protrusions 20 are configured to fit into wells 16.
  • microplate lid 12 covers microplate 10 in its entirety, and a well-interface protrusion 20 is provided to correspond to each of the 96 wells in microplate 10. However, in some embodiments of the invention, there may not be a well-interface protrusion corresponding to each well 16.
  • FIG. 2 is a detail view of a single well-interface protrusion 20. Opening 22 and opening 24 in underside 26 of protrusion 20 connect to microchannel 28 and microchannel 30, respectively. MicroChannel 28 and microchannel 30 (illustrated by dashed lines) may connect to additional microfluidic circuitry (not shown) in base structure 18 of microplate lid 12. The size and shape of protrusion 20 may vary depending on the application for which the lid is designed.
  • FIGS. 3 and 4 show cross sections of two embodiments of the microfluidic interface microplate lid, illustrating how it may interface with a microplate.
  • microplate lid 12 is formed of three layers.
  • Microplate interface layer 32 contacts the microplate 10 directly and forms the outer surface of well-interface protrusion 20 that fits into well 16 of the plate.
  • Middle layer 34 lies adjacent microplate interface layer 32 opposite the side that contacts microplate 10.
  • Channels and fluid control elements used in the specific application of the lid are formed at the interface between the microplate interface layer and the middle layer.
  • channel 28 with opening 22 and channel 30 with opening 24 are shown.
  • Channel 28 may be an inlet channel that is in fluid communication with a fluid inlet in the microplate lid, and which delivers fluid into space 25 in well 16.
  • Channel 30 may be an outlet channel through which fluid (or air) leave space 25 and is delivered to downstream features, which may include air escape vents, waste fluid reservoirs, fluid outlets, additional microfluidic circuitry, and possibly, other microplate wells. Also shown are channel narrowings 46 and 48, which may function as passive valves.
  • microplate interface layer 32 and middle layer 34 are designed to be disposable.
  • a top plate 36 which is designed to be re-usable, fits on top of these two layers. Top plate 36 may contain active elements, such as heating element 37, as shown here, or mechanical valves or sensors, to assist in controlling the lid function.
  • Top plate 36 includes protrusion 50, which fits inside protrusion 52 of middle layer 34, which similarly fits inside protrusion 20 defined by microplate interface layer 32.
  • Protrusion 20 fits closely against the interior of well 16 at sealing region 23, to form a sealed (or substantially sealed) enclosed space 25.
  • Enclosed space 25 may have an air-tight seal or a water-tight seal, depending on the requirements for the device.
  • sealing region 23 is a circular region where the edge of interface protrusion 20 contacts the interior of well 16.
  • the seal could be formed along a fairly narrow region 23, as depicted in FIGS. 3 and 4, or the seal could be formed along a larger contact area if the interface protrusion 20 conforms more closely to the interior of well 16.
  • microplate interface layer 32 and top plate 56 there are only two layers: microplate interface layer 32 and top plate 56, with no middle layer.
  • channels 28 and 30 and fluid control elements 62 and 64 are formed at the interface between microplate interface layer 32 and top plate 56.
  • the cross section is taken through a channel between microplate interface layer 32 and the adjacent layer, and therefore these layers are separated by the width of the channel except in the region between opening 22 and opening 24; in others regions of the device, the microplate interface layer directly contacts and is adhered or sealed to the adjacent layer.
  • FIG. 5 depicts microplate interface layer 32 with upper surface 66 exposed; the adjacent layer is not shown.
  • Microchannels 68, 70, 72, 28a, 28b and 30 are formed in upper surface 66.
  • Main channel 68 branches at branch point 69 into channels 70 and 72.
  • Main channel 68 may be connected to a fluid inlet, through which fluid is introduced into the base structure of the microplate lid.
  • the fluid inlet would connect at the edge of the microplate lid, but the invention may also include one or more fluid inlets that connect to the microfluidic circuitry of the microplate lid from the top plate or via other portions of the microplate lid.
  • Channel 70 connects to channel 28a, which extends into interface protrusion 20a.
  • Channel 72 connects to channel 28b, which extends into interface protrusion 20b.
  • Channel 30 also extends into interface protrusion 20a.
  • Channel 30 may be, for example, a second channel through which fluid exits the well to additional downstream features, or to a downstream fluid outlet, or it may be an air vent that allows air, but not fluid, to escape as the well is filled with fluid. Openings (not shown) at the ends of channels 28a and 30a permit the channels to communicate with the well in which the interface protrusion 20a is positioned.
  • opening 22b at the lower surface of interface protrusion 20b provides fluid communication between channel 28b and the well in which protrusion 20b is positioned.
  • microfluidic channels are formed in the microplate interface layer, and sealed by the adjacent layer, microfluidic structures can be formed in other layers of the microplate lid, as well.
  • microfluidic structure may be formed in several, overlapping layers in order to form three-dimensional microfluidic circuit structures.
  • the protrusions of the microfluidic interface microplate lid are designed to be inserted into the wells of the microplate and to control the volume of the well that is to be used.
  • the protrusion will typically fit closely in and seal with the well.
  • Some protrusions are designed to deliver fluid into a well; others are designed not only to deliver fluid, but also to remove fluid once a reaction has taken place.
  • the lid is designed to control the movement of fluid and air within the well-lid system.
  • Each protrusion has a fluid outlet, through which fluid is delivered to the microplate well, and an inlet, which may be used for the removal of fluid or release of air from the microplate well. By using a smaller diameter inlet, flow of fluid back into the microplate lid from the well may be prevented, while air flow is still permitted.
  • the microfluidic interface microplate lid may include multiple air or fluid ducts for each well, possibly of different protruding depths and diameters, to allow for whatever fluid control or transport is required.
  • the protrusion may be in a shape resembling a corkscrew, as shown in perspective view in FIG. 6.
  • the protrusion 80 is configured to conform closely to the interior surface of the whole well.
  • a spiral groove 82 in the outer surface of protrusion 80 forms a spiral channel, which has an outer wall formed by the wall of the microplate well. Fluid enters the spiral channel from channel 81 that runs between microplate interface layer 88 and middle layer 90, via opening 83.
  • a seal is formed between neck region 85 of protrusion 80 and the interior of the well in which it is placed, as well as along the spiral ridge formed by the exterior surface 87 of protrusion 80.
  • Fluid may be passed through the spiral channel around the exterior of protrusion 80 until it reaches the bottom of the well.
  • Protrusion 80 occupies most of the volume of the well, and the substantially sealed space that will be formed by the spiral channel and the bottom of the well will be relatively small.
  • FIG. 8 is a cross-sectional view of a "straw" type design in which fluid may be removed from the well via a straw type extension 94 of protrusion 20. Fluid enters space 95 formed in well 16 via a hole 22, which communicates with channel 28 in interface layer 32. When it is desired to remove the fluid, additional fluid is injected into well 16 through the upper hole 22, thus forcing the fluid already present in space 95 out, through hole 96 in straw type extension 94 and then through channel 30.
  • FIG. 9 shows an example of a microplate lid 98 that interfaces with only two centrally located rows 100 and 102 of a plate 10. Fluid inlet 101 and outlet 103 are also depicted. Microchannels connecting inlet 101 and outlet 103 with wells 16 are also illustrated.
  • the microplate lid may cover a region of a plate but not include protrusions that fit into the wells in that portion of the plate.
  • the microplate lid simply passes over certain wells and does not interface with them. This may be done if a well is not needed at that location for a particular application, and/or if the area within the lid is instead used for some kind of fluid control function.
  • the microfluidic interface microplate lid may contain wells or reaction chambers in addition to those present in the microplate, so that reactions may be performed within the lid.
  • FIG. 10 and 11 show exemplary configurations of microplate wells and microfluidic circuitry (located in the microplate lid overlying the wells).
  • microplate wells are represented by large circles, microfluidic channels which carry fluids are represented by heavy lines, and channels for air flow are represented by lighter lines.
  • four wells 104,106, 108, and 110 are available, but the microfluidic circuitry accesses only three of the wells. Fluid is delivered into well 106 via channel 112, and then it is moved out of well 106 via channel 114, which branches into channels 116 and 118, which deliver fluid to wells 108 and 110, respectively.
  • FIG. 10 gives an example of simple microfluidic circuitry (i.e., for dividing a fluid stream) downstream of microplate well 106, and leading to additional microplate wells (108 and 110).
  • Air ducts 120 and 122 which merge into air duct 123, allow air to escape from wells 108 and 110 as they are filled with fluid.
  • two of the wells, 124 and 126 are bypassed.
  • the microfluidic circuitry in the microplate lid includes channel 132 leading to well or reaction chamber 134 for processing of fluids prior to delivery into microplate wells 128 and 130, via channels 136, 138 and 140.
  • Reaction chamber 134 is a simple example of microfluidic processing circuitry that can be located upstream of microplate wells (in this case, wells 128 and 130). As in the circuit of FIG.
  • Reaction chamber 134 could contain a reactant or reagent (e.g., in lyophilized form) for performing a pre-processing step with fluid before it is delivered to wells in the microplate.
  • a reactant or reagent e.g., in lyophilized form
  • the most critical part of this system is the point of contact between the microplate well 16 and interface protrusion 20 from interface layer 32. It is important that there is not leakage of fluid between these surfaces. In some applications, leakage of air is to be avoided, as well.
  • This point of contact between the microplate well and protrusions on the interface layer can be reversibly "sealed" by making the interface layer, at least at this location, out of a soft, rubberized, plastic such as silicone rubber or polyurethane. A soft coating on a harder base plastic may also serve this function. It is also useful for this interface to be hydrophobic, so if there is a gap its effect will be minimized.
  • the top plate can be designed so that it provides downward pressure to affect the reversible seal.
  • microplate interface layer and middle layer may be sealed together physically, or they may be pressed together by the top plate as described above. It is critical that these two layers effectively contain fluid within the channels and chambers as designed, and that no leaking takes place. Similar materials and techniques may be used to prevent leakage as described in the previous paragraph.
  • the middle layer and microplate interface layer may also be designed to "snap" together using a series of interdigitated members that fit together and define the channel space between them. If the microplate were custom made it is also possible that the interface layer and microplate could "snap” together as well. However, it is anticipated that the microfluidic interface microplate lid will most frequently be used with standard, "off the shelf microplates, and is to be usable without requiring modifications to the microplate design.
  • FIG. 12 is a schematic of the distribution of a fluid sample to sixteen wells 16 in a 2- dimensional planar substrate.
  • fluid is delivered to the wells via the channels indicated by the darker lines. Fluid enters at inlet channel 142, splitting into first generation daughter channels 144, second generation daughter channels 146, third generation daughter channels 148, and fourth generation daughter channels 150, which lead to individual wells 16.
  • the channels indicated by lighter lines allow air to be displaced from the wells as fluid enters, and, in this case, are not designed to transport fluid.
  • multiple generations of channels 152, 154, 156, and 158 join, eventually all merging to form main air escape channel 160. Passive valving of the type described in U.S.
  • Patent 6,296,020 issued October 2, 2001 , or remote valving as described in PCT International Patent Publication No. WO 02/12734, may be used to control the flow of the fluid in channels leading to the wells so the sample may be distributed evenly or aliquoted to the wells in any desired volumes, and to ensure that the sample fills each well without flowing beyond the well.
  • FIG. 13 and 14 illustrate two possible channel layouts that could be used for distributing fluid in a microfluidic interface microplate lid.
  • the circuit of FIG. 13 is not truly equivalent to the layout of FIG. 12, but is substantially functionally equivalent in the cases where the volume of the sample to be distributed is greater than the total fluid containing volume of the channels and wells combined.
  • inlet channel 170 divides into two channels 172 and 174, each of which delivers fluid to multiple wells 16 in series, it is not possible to deliver fluid to individual wells selectively.
  • Delivery channels 175 extend from channels 172 and 174 to individual wells 16 and branch off of channels 172 and 174 at intervals. If the sample volume is greater than the total volume of the channels and wells, all wells can be filled uniformly with sample and this relatively simpler layout is sufficient.
  • each well 16 is an equal distance from the inlet channel 170.
  • a volume of sample just sufficient to fill all the wells can be injected into inlet 170 and then followed by a buffer solution or by air to push the sample into the wells and take up the dead volume of the channels in the lid.
  • Valves can be used to direct the flow of fluid at each generation of branches to ensure that fluid is distributed uniformly among the channels and, ultimately, among all the wells 16.
  • fluid flows through first generation daughter channels 180 and 182, second generation daughter channels 183, 184, 185 and 186, third generation daughter channels 187, 188, 189, 190, 191, 192, 193, and 194, and fourth generation daughter channels 195, 196, 210 before entering wells 16.
  • Passive valves are used in the presently preferred embodiment of the invention, but remote valves, as discussed above, or other types of valves may be used instead.
  • Microfluidic circuitry present in the microfluidic interface microplate lid could be used to distribute the sample and PCR components to each well, seal the fluid within the wells to prevent fluid movement or evaporation, and then push the fluid into additional wells for further processing if desired once PCR is complete.
  • Previous work has described how a plate can be sealed by pressurizing the fluidic system to prevent or eliminate evaporation.
  • the lid could be mechanized so that it physically shuts off the well outlet channels.
  • microfluidic interface microplate lid may include active heating or cooling elements, or both, to reduce thermal gradients that may reduce the effectiveness of the thermal process taking place in the microplate wells.
  • active heating or cooling elements or both, to reduce thermal gradients that may reduce the effectiveness of the thermal process taking place in the microplate wells.
  • Various methods could be used to heat or cool the lid, as are known by those familiar with this technology.
  • the microfluidic interface microplate lid may contain various active elements such as plungers to open or close channels or to push fluid, and it may contain other types of mechanical valving, pumps, heaters or sensors.
  • the top plate of the microfluidic interface microplate lid would generally be made of durable materials, such as metal or hard plastics, may have several permanent fixtures, such as valves and sensors, and may be a machined or injection molded piece.
  • the microplate interface layer and middle layer may be formed by embossing, blow molding, injection molding, or other similar processes. Some of the features in these layers could be laser machined as well.
  • the materials for these layers must be selected to provide physical and chemical properties suitable for the application for which they are designed. Such parameters would be known to someone skilled in the art of materials manufacturing.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Dispersion Chemistry (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)

Abstract

L'invention concerne un couvercle de microplaque (12), contenant des structures de transport et de traitement de liquide, permettant de délivrer de façon régulière de faibles volumes d'échantillons et de réactifs à une microplaque (10) et empêchant qu'une évaporation puisse se produire durant le fonctionnement.
PCT/US2002/006942 2001-03-09 2002-03-07 Couvercle de microplaque WO2002072423A1 (fr)

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US27439001P 2001-03-09 2001-03-09
US60/274,390 2001-03-09

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WO2003015920A2 (fr) * 2001-08-14 2003-02-27 Investigen, Inc. Couvercle de support d'echantillons
WO2003062133A2 (fr) * 2002-01-18 2003-07-31 Avery Dennison Corporation Structures de microchambres recouvertes
WO2003026797A3 (fr) * 2001-09-21 2003-09-18 Solvias Ag Systeme de scellement pourvu de canaux d'ecoulement
EP1364710A2 (fr) * 2002-05-13 2003-11-26 Becton, Dickinson and Company Plaque de stockage d'échantillon avec système de distribution d'aliquotes
DE10260690A1 (de) * 2002-12-23 2004-07-08 Technische Universität München Abdeckung für eine Vorrichtung, damit abgedeckte Vorrichtung und Verfahren zur parallelen, automatisierten Kultivierung von Zellen unter technischen Bedingungen
WO2004094060A1 (fr) * 2003-04-22 2004-11-04 Chip-Man Technologies Oy Appareil d'analyse et de mise en culture
WO2005012561A1 (fr) 2003-08-01 2005-02-10 Capital Biochip Company Ltd. Dispositifs a microreseau a volume de reaction controlable
DE10329983A1 (de) * 2003-06-27 2005-03-31 Siemens Ag Mikroreaktorsystem mit einer Reaktionsräume aufweisenden Trägerplatte und Verfahren zum Betrieb desselben
DE10346451A1 (de) * 2003-10-03 2005-05-12 Bionas Gmbh Verfahren und Versorgungseinheit zur Überwachung von Veränderungen und Zuständen in Reaktionskammern
EP1771545A1 (fr) * 2004-07-09 2007-04-11 Chip-Man Technologies Oy Sous-structure pour la culture de cellules et son utilisation
US7208125B1 (en) 2002-06-28 2007-04-24 Caliper Life Sciences, Inc Methods and apparatus for minimizing evaporation of sample materials from multiwell plates
WO2007120515A1 (fr) * 2006-04-07 2007-10-25 Corning Incorporated Microplaque fermée à écoulement continu et modes d'utilisation et procédés de fabrication de celle-ci
DE102006030068A1 (de) * 2006-06-28 2008-01-03 M2P-Labs Gmbh Vorrichtung und Verfahren zur Zu- und Abfuhr von Fluiden in geschüttelten Mikroreaktoren Arrays
WO2008008149A2 (fr) * 2006-07-13 2008-01-17 Seahorse Bioscience Appareil et méthode d'analyse de cellules
DE102006040562A1 (de) * 2006-08-30 2008-03-20 Pieter Van Weenen & Co. Gmbh The House Of Innovation Begasungssystem und -Verfahren
EP2135626A1 (fr) * 2008-06-19 2009-12-23 Eppendorf Array Technologies SA Bande pour analyses multiparamétriques
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DE102009036695B3 (de) * 2009-08-07 2011-04-07 Hp Medizintechnik Gmbh Einsatz für ein Well in einer Multiwellplatte und dessen Verwendung
US7981668B2 (en) * 2006-01-18 2011-07-19 Kci Licensing Inc. System and method for applying reduced pressure to cell culture
US8202702B2 (en) 2008-10-14 2012-06-19 Seahorse Bioscience Method and device for measuring extracellular acidification and oxygen consumption rate with higher precision
US8911995B2 (en) 2007-08-22 2014-12-16 Probiogen Ag Culture system and method for immunogenicity and immunofunction testing in vitro
WO2014205447A2 (fr) 2013-06-21 2014-12-24 Bio-Rad Laboratories, Inc. Système microfluidique ayant des organes de collecte de fluide
US9494577B2 (en) 2012-11-13 2016-11-15 Seahorse Biosciences Apparatus and methods for three-dimensional tissue measurements based on controlled media flow
LU100171B1 (de) * 2017-04-13 2018-10-15 Cytena Gmbh Vorrichtung zur Prozessierung einer flüssigen Probe
LU100170B1 (de) * 2017-04-13 2018-10-15 Cytena Gmbh Verfahren zum Prozessieren einer flüssigen Probe
US10118177B2 (en) 2014-06-02 2018-11-06 Seahorse Bioscience Single column microplate system and carrier for analysis of biological samples
EP3625136A4 (fr) * 2017-05-16 2021-01-13 Agilent Technologies, Inc. Couvercle de plaque de microtitration éliminant le vide et procédé de mesure optique de la concentration d'oxygène de puits à travers le couvercle
US11207685B2 (en) 2017-02-13 2021-12-28 Bio-Rad Laboratories, Inc. System, method, and device for forming an array of emulsions
CN113916641A (zh) * 2016-03-02 2022-01-11 霍夫曼-拉罗奇有限公司 用于分离的装置
EP3988924A3 (fr) * 2020-10-23 2022-07-20 BMG Labtech GmbH Lecteur de microdisques
WO2022233934A3 (fr) * 2021-05-06 2023-03-09 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e. V. Tête de dosage et système de dosage servant à la réception et au dosage d'au moins deux milieux
US11639925B2 (en) 2017-04-06 2023-05-02 Agilent Technologies, Inc. Method and apparatus for measuring physiological properties of biological samples

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US7152492B2 (en) 2001-08-14 2006-12-26 Investigen, Inc. Lid for sample holder
WO2003015920A3 (fr) * 2001-08-14 2004-03-04 Investigen Inc Couvercle de support d'echantillons
WO2003015920A2 (fr) * 2001-08-14 2003-02-27 Investigen, Inc. Couvercle de support d'echantillons
US7504071B2 (en) 2001-09-21 2009-03-17 Solvias Ag Sealing system with flow channels
WO2003026797A3 (fr) * 2001-09-21 2003-09-18 Solvias Ag Systeme de scellement pourvu de canaux d'ecoulement
WO2003062133A2 (fr) * 2002-01-18 2003-07-31 Avery Dennison Corporation Structures de microchambres recouvertes
WO2003062133A3 (fr) * 2002-01-18 2003-12-24 Avery Dennison Corp Structures de microchambres recouvertes
US7514045B2 (en) 2002-01-18 2009-04-07 Avery Dennison Corporation Covered microchamber structures
EP1364710A2 (fr) * 2002-05-13 2003-11-26 Becton, Dickinson and Company Plaque de stockage d'échantillon avec système de distribution d'aliquotes
US7354774B2 (en) 2002-05-13 2008-04-08 Becton, Dickinson And Company Self aliquoting sample storage plate
EP1364710A3 (fr) * 2002-05-13 2006-03-22 Becton, Dickinson and Company Plaque de stockage d'échantillon avec système de distribution d'aliquotes
US7208125B1 (en) 2002-06-28 2007-04-24 Caliper Life Sciences, Inc Methods and apparatus for minimizing evaporation of sample materials from multiwell plates
DE10260690A1 (de) * 2002-12-23 2004-07-08 Technische Universität München Abdeckung für eine Vorrichtung, damit abgedeckte Vorrichtung und Verfahren zur parallelen, automatisierten Kultivierung von Zellen unter technischen Bedingungen
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CN100408188C (zh) * 2003-04-22 2008-08-06 奇普-曼科技股份有限公司 分析及培养仪器及其盖
WO2004094060A1 (fr) * 2003-04-22 2004-11-04 Chip-Man Technologies Oy Appareil d'analyse et de mise en culture
DE10329983A1 (de) * 2003-06-27 2005-03-31 Siemens Ag Mikroreaktorsystem mit einer Reaktionsräume aufweisenden Trägerplatte und Verfahren zum Betrieb desselben
US8293519B2 (en) 2003-08-01 2012-10-23 Capitalbio Corporation Microarray devices having controllable reaction volume
WO2005012561A1 (fr) 2003-08-01 2005-02-10 Capital Biochip Company Ltd. Dispositifs a microreseau a volume de reaction controlable
EP1649046A4 (fr) * 2003-08-01 2010-06-23 Capitalbio Corp Dispositifs a microreseau a volume de reaction controlable
EP1649046A1 (fr) * 2003-08-01 2006-04-26 Capital Biochip Company Ltd Dispositifs a microreseau a volume de reaction controlable
US7851201B2 (en) 2003-09-10 2010-12-14 Seahorse Bioscience, Inc. Method and device for measuring multiple physiological properties of cells
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US7638321B2 (en) 2003-09-10 2009-12-29 Seahorse Bioscience, Inc. Method and device for measuring multiple physiological properties of cells
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DE10346451B4 (de) * 2003-10-03 2007-08-02 Bionas Gmbh Verfahren zur Überwachung von Veränderungen und Zuständen in Reaktionskammern
EP1771545A1 (fr) * 2004-07-09 2007-04-11 Chip-Man Technologies Oy Sous-structure pour la culture de cellules et son utilisation
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US7981668B2 (en) * 2006-01-18 2011-07-19 Kci Licensing Inc. System and method for applying reduced pressure to cell culture
WO2007120515A1 (fr) * 2006-04-07 2007-10-25 Corning Incorporated Microplaque fermée à écoulement continu et modes d'utilisation et procédés de fabrication de celle-ci
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US8658349B2 (en) 2006-07-13 2014-02-25 Seahorse Bioscience Cell analysis apparatus and method
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US8911995B2 (en) 2007-08-22 2014-12-16 Probiogen Ag Culture system and method for immunogenicity and immunofunction testing in vitro
EP2183353B1 (fr) * 2007-08-22 2015-04-29 ProBioGen AG Système de culture et procédé pour tester l'immunogénicité et l'immunofonction in vitro
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US8202702B2 (en) 2008-10-14 2012-06-19 Seahorse Bioscience Method and device for measuring extracellular acidification and oxygen consumption rate with higher precision
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DE102009036695B3 (de) * 2009-08-07 2011-04-07 Hp Medizintechnik Gmbh Einsatz für ein Well in einer Multiwellplatte und dessen Verwendung
US9494577B2 (en) 2012-11-13 2016-11-15 Seahorse Biosciences Apparatus and methods for three-dimensional tissue measurements based on controlled media flow
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WO2014205447A2 (fr) 2013-06-21 2014-12-24 Bio-Rad Laboratories, Inc. Système microfluidique ayant des organes de collecte de fluide
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JP7110300B2 (ja) 2013-06-21 2022-08-01 バイオ－ラッド・ラボラトリーズ・インコーポレーテッド 流体ピックアップを備えるマイクロ流体システム
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EP3011302A4 (fr) * 2013-06-21 2017-01-18 Bio-rad Laboratories, Inc. Système microfluidique ayant des organes de collecte de fluide
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US10682647B2 (en) 2013-06-21 2020-06-16 Bio-Rad Laboratories, Inc. Microfluidic system with fluid pickups
JP2016528027A (ja) * 2013-06-21 2016-09-15 バイオ−ラッド・ラボラトリーズ・インコーポレーテッド 流体ピックアップを備えるマイクロ流体システム
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US10118177B2 (en) 2014-06-02 2018-11-06 Seahorse Bioscience Single column microplate system and carrier for analysis of biological samples
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US11207685B2 (en) 2017-02-13 2021-12-28 Bio-Rad Laboratories, Inc. System, method, and device for forming an array of emulsions
US11639925B2 (en) 2017-04-06 2023-05-02 Agilent Technologies, Inc. Method and apparatus for measuring physiological properties of biological samples
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JP2020516913A (ja) * 2017-04-13 2020-06-11 ツィテナ ゲーエムベーハーＣｙｔｅｎａ Ｇｍｂｈ 液状試料の処理装置
WO2018189398A1 (fr) * 2017-04-13 2018-10-18 Cytena Gmbh Dispositif de traitement d'un échantillon liquide
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