EP1165234A1 - Systeme de transfert de liquides et procede associe - Google Patents

Systeme de transfert de liquides et procede associe

Info

Publication number
EP1165234A1
EP1165234A1 EP00911980A EP00911980A EP1165234A1 EP 1165234 A1 EP1165234 A1 EP 1165234A1 EP 00911980 A EP00911980 A EP 00911980A EP 00911980 A EP00911980 A EP 00911980A EP 1165234 A1 EP1165234 A1 EP 1165234A1
Authority
EP
European Patent Office
Prior art keywords
plunger
syringe
needle
liquid
assembly
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00911980A
Other languages
German (de)
English (en)
Inventor
Jeffrey H. Sugarman
Haim Kedar
Andrew J. Kelly
Marcel Van Den Bronk
Ernest Dawes
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SGE International Pty Ltd
Glaxo Group Ltd
Original Assignee
SGE International Pty Ltd
Glaxo Group Ltd
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 SGE International Pty Ltd, Glaxo Group Ltd filed Critical SGE International Pty Ltd
Publication of EP1165234A1 publication Critical patent/EP1165234A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L9/00—Supporting devices; Holding devices
    • B01L9/54—Supports specially adapted for pipettes and burettes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00279—Features relating to reactor vessels
    • B01J2219/00306—Reactor vessels in a multiple arrangement
    • B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00279—Features relating to reactor vessels
    • B01J2219/00306—Reactor vessels in a multiple arrangement
    • B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
    • B01J2219/00315—Microtiter plates
    • B01J2219/00317—Microwell devices, i.e. having large numbers of wells
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00351—Means for dispensing and evacuation of reagents
    • B01J2219/00373—Hollow needles
    • B01J2219/00376—Hollow needles in multiple or parallel arrangements
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00585—Parallel processes
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N2035/00178—Special arrangements of analysers
    • G01N2035/00237—Handling microquantities of analyte, e.g. microvalves, capillary networks
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1065—Multiple transfer devices
    • G01N35/1074—Multiple transfer devices arranged in a two-dimensional array

Definitions

  • the invention relates generally to the field of liquid dispensing, and in particular to the dispensing of liquids into relatively small wells. More specifically, the invention provides for the dispensing of precise volumes of liquid into plates having a high density of wells.
  • the wells which receive the liquids are often formed in plates having a standard arrangement or format.
  • one common format is a 96 well format where the plate is generally rectangular in geometry and has its wells arranged in eight rows and twelve columns. The outer dimensions of such plates are typically about 8.53 cm by about 12.78 cm.
  • the wells are disposed within a rectangular area of about 80 cm 2 .
  • Another common well format is a 384 well format which has 384 wells in the same area utilized by 96 well formats. As such, the 384 well format has a higher density of wells.
  • multi-well plates are well known within the art and are available from a host of commercial suppliers, such as Polyfiltronics.
  • the use of standard sized plates is advantageous because such plates may be used with most commercially available handling and processing equipment. For example, most automated plate readers, some speed vacuum concentrators, autosamplers. robotics liquid handling equipment, and the like, are configured to operate with standard 96 and 384 multi-well plate formats.
  • automated dispensing systems which are employed to dispense fluids into the wells of such plates.
  • 864 well format Another type of format that is becoming increasingly useful is an 864 well format having 24 rows and 36 columns of wells which are disposed in the same area utilized by 96 well plates.
  • the use of 864 well formats is becoming more popular as the need to evaluate larger chemical libraries in a more efficient manner increases. Reduction in the size of the wells is also advantageous because less chemicals (which can often be relatively expensive) are needed.
  • the 864 well format has outer dimensions similar to 96 and 384 well formats to take advantage of existing automated equipment.
  • a liquid dispenser which comprises a base member and at least 864 syringes which are operably coupled to the base member.
  • the syringes are each configured to aspirate and dispense a substantially equal volume of liquid.
  • each syringe has a distal tip, with the syringe tips being disposed within an area that is less than about 80 cm " .
  • 864 or more syringes may be used to transfer liquids to wells of multi-well plates having at least 864 wells which are disposed within an area similar to most 96 and 384 multi-well plates.
  • the liquid dispenser has a high density of syringes so that all 864 wells of an 864 well plate may simultaneously be filled with a metered volume of liquid.
  • each syringe is configured to aspirate and dispense liquids having a volume in the range from about 10 nl to about 10 ⁇ l.
  • an actuation assembly is preferably provided to actuate aspiration and dispensing of the liquid.
  • a hydrophobic coating is disposed on a distal tip and an outside surface of each syringe.
  • the hydrophobic coating may comprise a silicone based coating.
  • Such a coating is particularly useful when dispensing volumes that are less than about 1 ⁇ l into a dry well.
  • the hydrophobic coating ensures that the liquid is dispensed in droplet form, without adhering to the distal tip or the outer surface of the syringe. In this way, the droplet may be contacted with a bottom end of a well to transfer the liquid into the well when the syringe tip is moved away from the bottom end of the well.
  • the invention provides a liquid dispensing system which comprises a base member, and a movable mount movably coupled to the base member.
  • a plurality of syringe units are removably mounted to the mount, and each syringe unit includes an array of syringes. Further, the syringes are each configured to aspirate and dispense a liquid upon movement of the mount.
  • a tray is provided which is configured to receive a multi- well plate.
  • the tray may be configured to move the multi-well plate such that the syringes are placed into the wells of the plate.
  • a robot may be employed to deliver and position a multi-well plate relative to the syringes.
  • each syringe unit or module includes a 24 by 4 array of syringes, and the moveable mount is configured to hold nine syringe units. In this way, 864 syringes are provided so that all 864 wells of an 864 well plate may simultaneously receive a liquid.
  • each syringe includes a syringe body and a plunger which is movable within the syringe body to aspirate liquids into the syringe body and to dispense liquids from the syringe body.
  • each plunger is operably coupled to the moveable mount such that movement of the moveable mount moves the plungers within the syringe bodies.
  • a proximal portion of each syringe body is collapsible when the mount is moved to move the plungers.
  • the proximal collapsible portion may comprise a tubular outer guide which slides over a tubular inner guide when the mount is moved.
  • a fixed mount is preferably also provided to hold a distal portion of the syringe bodies.
  • the invention further provides an exemplary syringe assembly which comprises at least one tubular plunger guide and a needle coupled to the plunger guide.
  • the needle includes a lumen which terminates at an open distal tip.
  • the assembly further includes a plunger that is moveable within the plunger guide and the needle.
  • a sealing mechanism is disposed to form a seal between the needle and the plunger guide and between the plunger and the seal member. In this way, liquids may be aspirated into the lumen of the needle when the plunger is retracted, and liquids may be dispensed from the lumen of the needle when the plunger is extended.
  • the syringe assembly preferably includes a pair of tubular plunger guides, with one of the guides being an inner guide and the other being an outer guide.
  • the inner guide is disposed within the outer guide, and the plunger guides slide relative to each other during movement of the plunger.
  • a guide plate may be disposed to maintain the inner and outer plunger guides in axial alignment.
  • the syringe assembly may also include a center plate and a lower plate which are fixed relative to each other. With this configuration, the needle is held by the lower plate, and the inner guide is held by the middle plate.
  • a top plate is preferably also provided, and both the outer guide and the plunger are preferably coupled to the top plate. Further, the top plate is moveable relative to the middle plate to move the plunger within the needle.
  • a stop is provided to limit the movement of the top plate relative to the center plate. In this way, the amount of travel of the plunger may be controlled.
  • the sealing mechanism comprises a tubular seal member disposed between the inner plunger guide and the needle. The sealing mechanism further includes a protrusion that is coupled to the inner guide, and a biasing member that is disposed between the center plate and the protrusion to force the inner plunger guide against the seal member.
  • the needle has a distal portion with an outer diameter that is less than about 0.7 mm when used to dispense volumes of about 5 ⁇ l, and less than about 0.8 mm when used to dispense volumes of about 10 ⁇ l.
  • the needle is capable of dispensing liquids having a volume in the range from about 10 nl to about 10 ⁇ l.
  • the distal tip and the outer surface of the needle may be provided with a hydrophobic coating.
  • the invention provides an exemplary syringe assembly unit having a plurality of syringe assemblies which are constructed similar to those just described.
  • the syringe assembly unit further comprises a holding system to hold the syringe assemblies.
  • the holding system comprises a sliding mount and a fixed mount. In this way, the plungers may be moved within the needles by moving the sliding mount relative to the fixed mount.
  • One advantage of utilizing the holding system is that multiple syringe assembly units may be held within the sliding mount so that a relatively large number of needles may be provided within a relatively small space. For example, the needle tips may be spaced apart by a distance as small as about 1 mm.
  • the sliding mount is slidably coupled to a track, and a motor is provided to move the slidable amount along the track. In this way, all of the syringe assemblies which are coupled to the mount may have a liquid dispensed simply by operating the motor to move the mount.
  • the invention further provides an exemplary method for dispensing liquids.
  • a plate is provided having at least 864 wells. Further, the wells are disposed in an area that is less than about 80 cm 2 .
  • a liquid is aspirated into at least 864 syringes, and a substantially equal volume of liquid is dispensed from each of the syringes and into the wells of the plate.
  • a liquid having a volume in the range from about 10 nl to about 10 ⁇ l is dispensed from each syringe.
  • each syringe has a syringe body and a plunger that is disposed within the syringe body.
  • the liquid is aspirated by retracting the plunger within a distal portion of the syringe body, and the liquid is dispensed by extending the plunger within the distal portion.
  • a proximal portion of the syringe body is compressed to extend the plunger within the distal portion.
  • each plunger is initiated at substantially the same time, and each plunger is moved at substantially the same rate.
  • a substantially equal volume of liquid is dispensed at substantially the same time from each syringe.
  • the liquid is dispensed with a precision that is less than about 6% CV at about 0.1 ⁇ l per well.
  • the amount of liquid dispensed may be incremented m increments m the range from about 10 nl to about 10 ⁇ l.
  • the liquid to be transferred may be formed as a droplet by providing a hydrophobic coating on a distal tip and an outside surface of the sy ⁇ nge.
  • the sy ⁇ nges are moved in close proximity to a bottom end of the wells to permit the droplets to contact the bottom ends of the wells.
  • the sy ⁇ nges are then raised to transfer the droplets into the wells. Such a process is particularly useful when dispensing small volumes into dry wells.
  • Fig. 1 is a perspective view of an exemplary liquid dispensing system according to the invention.
  • Figs. 1A, IB and 1C are side, top and front views, respectively, of the system of Fig. 1.
  • Fig. 2 is a side view of a sy ⁇ nge assembly unit of the system of Fig. 1 which includes a plurality of sy ⁇ nge assemblies.
  • Fig. 3 is an end view of the unit of Fig. 2.
  • Fig. 4 is a top view of the unit of Fig. 2.
  • Fig. 5 is a side view of a plunger from one of the sy ⁇ nge assemblies of
  • Fig. 6 is a side view of an outer plunger guide from one of the sy ⁇ nge assemblies of Fig. 2.
  • Fig. 7 is a side view of an inner guide assembly from one of the sy ⁇ nge assemblies of Fig. 2.
  • Fig. 8 is a side view of a needle from one of the sy ⁇ nge assemblies of Fig. 2.
  • Fig. 9 is a cross sectional side view of a top portion of the unit of Fig. 2.
  • Fig. 10 is a cross sectional side view of a middle portion of the unit of Fig 2
  • Fig 11 illustrates the system of Fig 1 with dispensing needles being inserted into the wells of a multi-well plate, and with a moveable mount being raised to retract plungers withm the needles.
  • Fig 12 illustrates the system of Fig 1 1 with the moveable mount being lowered to extend the plungers withm the needles to dispense a liquid into the wells
  • the invention provides exemplary systems, assemblies and methods to aspirate and dispense liquids m relatively small volumes
  • the invention utilizes sy ⁇ nges which are relatively small in size and are spaced close together so that they can be used with multi-well plates having a high density of wells
  • all of the sy ⁇ nges are configured so that they may be actuated at substantially the same time
  • each sy ⁇ nge is able to aspirate and dispense at substantially the same time with substantially the same volume
  • plates having a relatively high density of wells may simultaneously have all of its wells simultaneously filled with a metered volume of liquid.
  • the invention will find its greatest use with multi-well plates having 864 wells that are disposed within an area of about 80 cm " As such, the 864 well plates may be constructed to have an outer pe ⁇ meter which is compatible with existing automated processing and handling equipment Although the invention will find its greatest use with 864 well plates, it will be appreciated that the invention is useful with other plates having different numbers of wells For example, m some cases the invention may be utilized with standard plates having less than 864 wells, e g , 96 and 384 well plates, as well as those having more than 864 wells, e g , 1536 well plates Moreover, it will be appreciated that the invention may be utilized with multiwell plates which do not have the same footp ⁇ nt utilized with existing 96 and 384 well plates As such, the invention may be modified to include essentially any number of sy ⁇ nges in a wide va ⁇ ety of arrangements so that it may be compatible with plates having essentially any number and/or arrangement of wells
  • the 864 well plates utilized with the invention preferably have wells that define a volume in the range from about 2 ⁇ l to about 20 ⁇ l
  • the use of such relatively small volumes is advantageous in that a minimal volume of liquid may be placed into each of the wells This is particularly advantageous with processes where the liquid is relatively expensive Bv minimizing the amount of liquid aspirated and dispensed, the expense of the process may be reduced
  • the use of such relatively small volumes allows for a relatively high densitv of wells withm a given area In this manner, the throughput of the system may be greatly increased since significantly more wells may be utilized within the same area.
  • the syringes of the invention are preferably configured so that they are able to dispense volumes in the range from about 10 nl to about 10 ⁇ l, and more preferably in the range from about 100 nl to about 10 ⁇ l.
  • This range of volumes may be dispensed into wells that already include fluid, or into dry wells.
  • the liquid forced out of the syringes may be contacted with the liquid to facilitate its transfer from the syringe.
  • the syringes may be provided with a hydrophobic coating on their distal tips and outside surfaces.
  • a hydrophobic coating is a silicone based coating.
  • the liquid when the liquid is forced out of the syringe, the liquid is prevented from contacting the distal tip and the outer surface, thereby forming a droplet.
  • This droplet may then be contacted against a dry bottom end of a well to transfer the droplet into the well.
  • the syringes are preferably configured so that they are able to deliver such volumes in increments as low as 10 nl and more preferably in the range from about 50 nl to about 2 ⁇ l.
  • syringes of the invention are able to deliver precise volumes of liquid, preferably less than about 6% CV for fill volumes in the range from about 100 nl to about 10 ⁇ l, it being appreciated that substantially lower CV percentages are obtainable within the higher fill volume ranges.
  • the syringes are preferably in arranged in units or modules.
  • each unit includes a two dimensional a ⁇ ay of syringes. Multiple units may then be combined together to form a system of syringes.
  • the number of syringes in the system may be varied simply by varying the number of syringes in the units and/or by varying the number of units.
  • each unit may include a 24 by 4 array of syringes, with the system including 9 syringe units.
  • other arrangements may be utilized.
  • the syringes of the invention preferably utilize a plunger which moves through a needle to displace a volume of liquid that is substantially equal to the volume displaced by the plunger. Similarly, the syringes aspirate liquids by retracting the plunger to create a vacuum within each needle. With such a construction, the syringes have zero dead volume so that all of the liquid that is aspirated is dispensed. Further, the volume aspirated and dispensed may be varied by varying the length of the stroke of the plunger and/or by varying the size of the plunger.
  • the plunger-in-needle design of the invention is also useful in reducing the amount of space between the needles to increase the density of the needles. In this way, liquids may efficiently be dispensed into plates having a high density of wells.
  • the needles of the invention may be spaced apart by a distance as small as 1 mm.
  • the distance between the needles is preferably about 3 mm.
  • the invention also utilizes a holding system which holds the syringes such that the needle tips remain precisely laterally spaced apart and remain positioned within the same plane during aspiration and dispensing.
  • the needle tips may repeatedly be positioned within all wells of a multi-well plate at a proper and consistent depth.
  • the variability in the position of the needle tips within a given plane is less than about 0.1 mm.
  • the syringe or needle tips are preferably placed into the wells of a multi- well plate by moving the syringe tips into the wells, by moving the multi-well plates relative to the syringe tips, or both.
  • a robot is utilized to grasp and deliver the multi-well plate to the dispensing system.
  • the arm of the robot is also used to position the plate such that the syringe tips are disposed within the wells.
  • one type of robot that may be utilized is an ESC-200 robot, commercially available from Equip Technologies.
  • System 10 is constructed of a base member 12 having a back plate 14. Securely coupled to back plate 14 is a fixed mount 16.
  • Fixed mount 16 includes a lip 18 onto which multiple syringe assembly units 20 are held. For convenience of illustration, only two of a possible 9 units are shown.
  • each syringe assembly unit 20 includes a plurality of syringes having needles whose distal tips extend below fixed mount 16. In this way, the needle tips may be introduced into the wells of a multi-well plate by placing the multi- well plate beneath fixed mount 16 and raising the multi-well plate until the needle tips are within the wells.
  • system 10 further includes a movable tray 22.
  • Tray 22 is movable in a vertical direction so that when a multi-well plate is positioned on tray 22, the multi-well plate may be lifted to have the needle tips placed within its wells.
  • Tray 22 is coupled to an arm 24 which in turn is slidably coupled to a track system 26 which is coupled to back plate 14.
  • a servo motor 28, having a lead screw (not shown) is employed to slide arm 24 vertically up and down along track system 26. In this way, motor 28 may be employed to vertically raise and lower tray 22 so that the multi-well plate may be properly positioned with respect to the needle tips of the syringes within units 20.
  • System 10 also includes a sliding mount 30 which is configured to move vertically up and down with respect to fixed mount 16.
  • Sliding mount 30 includes a lip 32 into which syringe assembly units 20 are also coupled.
  • units 20 are coupled to fixed mount 16 and to sliding mount 30 by use of clamps (not shown).
  • clamps not shown.
  • fastening mechanisms may be used including screws or other fasteners which are placed through fixed mount 16 and sliding mount 30, welds, and the like.
  • sliding mount 30 is lowered to dispense liquids from each of the syringes. Conversely, sliding mount 30 is raised relative to fixed mount 16 to create a vacuum within the syringes so that liquid may be aspirated into the syringes.
  • a protective cover plate is preferably disposed on top of sliding mount 30 after each of the syringe assembly units 20 has been inserted.
  • Sliding mount 30 is slidably coupled to a track system 34 which is coupled to back plate 14.
  • a servo motor 36 with a lead screw (not shown) is employed to vertically raise and lower sliding mount 30 along track system 34.
  • Exemplary motors which may be utilized for both motor 36 and motor 28 are AVS servo motors, commercially available from Bearing Engineers, Inc.
  • a control system may be coupled to motors 28 and 36 to control the amount of movement of tray 22 as well as sliding mount 30. As described in greater detail hereinafter, by controlling the amount of vertical movement of sliding mount 30, the volume of liquid aspirated or dispensed from the syringes may be precisely controlled.
  • An exemplary control system which may be utilized includes a Pentium- based personal computer which includes interface software and which is coupled to a controller. In turn, the controller is configured to send high voltage signals to an amplifier or driver which converts the voltage signal to current which drives the motors.
  • An exemplary controller which may be utilized is a DMC-1040 unit, commercially available from Galil.
  • An exemplary driver which may be utilized is an AVS driver, commercially available from Bearing Engineering, Inc.
  • Figs. 2-4 construction of one of the syringe assembly units 20 will be described in greater detail. First, the outer framework of unit 20 will be described. Second, a detailed discussion of the manner of construction of each syringe will be described.
  • Unit 20 is framed by utilizing a lower plate 38 and a center plate 40.
  • Both lower plate 38 and center plate 40 include a two dimensional array of through holes 42 and 44, respectively, through which syringe assemblies 46 are disposed.
  • unit 20 includes a 24 by 4 a ⁇ ay of syringe assemblies 46.
  • through holes 42 and 44 are 96 in number.
  • a pair of support posts 48 Positioned between lower plate 38 and center plate 40 are a pair of support posts 48. Screws 50 are employed to securely connect post 48 to both lower plate 38 and center plate 40. In this way, the position of lower plate 38 is fixed relative to center plate 40.
  • lower plate 38 is coupled to fixed mount 16 so that both the position of lower plate 38 and center plate 40 are fixed relative to mount 16 (as well as to back plate 14).
  • Lower plate 38 and center plate 40 are preferably constructed of a rigid material, such as aluminum.
  • Through holes 42 and 44 are fashioned to have a size sufficient to allow the relevant portions of syringe assemblies 46 to slide through the through holes as described in greater detail hereinafter.
  • top plate 52 Also framing syringe assembly unit 20 is a top plate 52. Coupled to top plate 52 by screws 54 are a pair of plunger stops 56. As shown, plunger stops 56 are resting upon center plate 40. As such, downward movement of top plate 52 relative to center plate 40 is prevented. Top plate 52 may be vertically raised relative to center plate 40 simply by lifting top plate 52.
  • top plate 52 is secured to sliding mount 30. In this way, as sliding mount 30 is vertically raised and lowered, top plate 52 is vertically raised and lowered with respect to both center plate 40 and lower plate 38. When plunger stops 56 engage center plate 40, further downward movement of sliding mount 30 is prevented.
  • top plate 52 includes a plurality of through holes 58 for receiving the sy ⁇ nge assemblies 46
  • Top plate 52 may be constructed of materials similar to those used for center plate 40 and lower plate 38
  • Guide plate 62 includes a plurality of through holes 64 which are sized such that the relevant portion of each sy ⁇ nge assembly 46 may slide through the through holes as desc ⁇ bed in greater detail hereinafter Guide plate 62 serves as a lateral support for sy ⁇ nge assemblies 46 when top plate 52 is raised and lowered
  • Each sy ⁇ nge assembly 46 is constructed of a plunger 66 (see Fig 5), an outer plunger guide 68 (see Fig 6), an inner plunger guide assembly 70 (see Fig 7), and a needle 72 (see Fig 8)
  • plunger 66 has a proximal end 74 which is secured to a set screw 76 (see Fig 9)
  • the through holes 58 in top plate 52 include a threaded portion 78 into which set screw 76 may be screwed In this way, plunger 66 may be securely coupled to top plate 52
  • Use of set screw 76 is advantageous in that the position of plunger 66 within needle 72 may be va ⁇ ed simply turning set screw 76 For example, in some cases, it may be desirable to have plunger 66 extend beyond needle 72 when dispensing to ensure the liquid is fully dispensed The extent of travel of the distal end of
  • each through hole 58 Resting a bottom portion of each through hole 58 is outer plunger guide 68 as best shown in Fig 9 Plunger guide 68 has a flared end which rests upon a lip at the bottom of through hole 58 In this way, the position of outer plunger guide 68 relative to top plate 52 is fixed
  • Outer plunger guide 68 is preferably constructed of a generally ⁇ gid mate ⁇ al, such as stainless steel Outer plunger guide 68 preferably has an outer diameter of about 1 3 mm, and an inner diameter of about 0 8 mm As shown in Fig 9, plunger 66 extends through outer plunger guide 68 Plunger 66 is preferably constructed of stainless steel, and has an outer diameter of about 0 36 mm
  • inner plunger guide assembly 70 comp ⁇ ses an inner plunger guide 80 o ⁇ er which an outer tube 82 is disposed Disposed over outer tube 82 is a projecting member 84
  • Inner plunger guide 80 is preferably constructed of stainless steel and has an outer diameter of about 0 64 mm and an inner diameter of about 0.365 mm. In this way, plunger 66 is able to slide within inner plunger guide 80.
  • Outer tube 82 is preferably constructed of stainless steel and is bonded to inner plunger guide 80.
  • Outer tube 82 preferably has an outer diameter of about 1.07 mm and an inner diameter of about 0.65 mm. The outer diameter of tube 82 is such that it may slide within through hole 42 of center plate 40.
  • Projecting member 84 is preferably tubular in geometry and is preferably bonded to outer tube 82.
  • Projecting member 84 is preferably constructed of stainless steel, and has an outer diameter of about 1.6 mm and an inner diameter of about 1.1 mm.
  • projecting member 84 is employed to contain a spring 86 between projecting member 84 and center plate 40.
  • spring 86 assists in producing a seal so that plunger 66 is able to efficiently aspirate and dispense liquids.
  • Needle 72 includes a proximal portion 88, and central portion 90 and a distal portion 92 which terminates at a tip 94.
  • Needle 72 is preferably constructed of stainless steel, and has an outer diameter of about 0.64 mm.
  • Securely disposed over central portion 90 are a pair of tubes 90a and 90b.
  • Tube 90a has an outer diameter which is larger than the diameter of through hole 44 so that it will rest on top of lower plate 38.
  • Tube 90b has a diameter which allows it to fit within through hole 44 as best shown in Fig. 2.
  • a central lumen 96 extends through needle 72.
  • Lumen 96 preferably has a diameter of about 0.365 mm. As best shown in Fig.
  • plunger 66 passes through lumen 96 and substantially fills lumen 96. In this way, plunger 66 is able to force substantially all of the liquid out of lumen 96 when translated through the lumen. In this manner, needle 72 has zero dead volume so that essentially all liquid aspirated is also dispensed.
  • needle 72 may include a hydrophobic coating on its outside surface and at tip 94. Such a coating is used to ensure that the liquid being dispensed will not adhere to tip 94 or the outside surface. In this way, the liquid will form a droplet as plunger 66 is translated through lumen 96.
  • Proximal portion 88 is slidable within outer tube 82 as best shown in Fig. 10. Disposed between proximal portion 88 and inner plunger guide 80 is a tubular seal member 98 as best shown in Fig. 10. Seal member 98 is preferably constructed of PTFE and has an outer diameter of about 0.63 mm and an inner diameter of about 0.36 mm. The inner diameter of seal member 98 is selected so that a seal is produced about plunger 66, while still allowing plunger 66 to translate through seal member 98. When assembled, bottom plate 38 forces proximal portion 88 against seal member 98. Also, spring 86 provides a compressive force, i.e.
  • a preload to compress seal member 98 between inner plunger guide 80 and proximal portion 88.
  • a seal is also provided between needle 72 and inner plunger guide assembly 70.
  • liquids as well as gasses are prevented from leaking beyond seal member 98.
  • Such a configuration is particularly advantageous when withdrawing plunger 66 from needle 72 to create a vacuum within needle 72 so that liquids may be aspirated into needle 72.
  • the preload provided by spring 86 allows seal member 98 to experience wear while still providing an effective seal between seal member 98 and plunger 66. In this way, maintenance of the unit is reduced.
  • Use of spring 86 is further advantageous in that it allows the inner plunger guide 80 to be spring loaded, rather than needle 72. In this way, the position of the distal tip of needle 72 may be fixed during dispensing to allow the needle tip to be more accurately positioned during dispensing.
  • lower plate 38 presses upward on tubes 90a which fixes the position of needle tips 94 relative to lower plate 38.
  • the distance of each tip 94 from lower plate 38 may be precisely controlled so that the needle tips 94 lie within the same plane.
  • the lateral spacing between tips 94 may be precisely controlled so that tips 94 may accurately be positioned within wells of a multiwell plate. Since tips 94 do not move during dispensing, the accuracy of the system when dispensing is greatly improved.
  • syringe assembly units 20 operate by lifting top plate 52 relative to center plate 40 to withdraw plunger 66 from lumen 96 of needles 72.
  • outer plunger guide 68 slides over inner plunger guide 80 so that plungers 66 remain protected by and supported by a guide.
  • Guide plate 62 also assists in maintaining plunger 66 axially straight when top plate 52 is raised and lowered.
  • top plate 52 is lowered relative to center plate 40. In so doing, plunger 66 forces the liquid from lumen 96. As such, the amount of movement of top plate 52 may be controlled to control the amount of liquid that is dispensed. As top plate 52 is lowered, outer plunger guide 68 slides over inner plunger guide 80 so that the plunger guides will not interfere with movement of the top plate 52. When the distal tip of plungers 66 reaches tips 94 of needle 72, plunger stops 56 engage center plate 40 to prevent further travel of top plate 52. Referring now to Figs.
  • Tray 22 is then raised until needles 72 are positioned within its wells as shown in Fig. 1 1.
  • Mount 30 is then moved from the position shown in Fig. 1 1 back to the position shown in Fig. 12 to dispense the liquid from the needles.
  • Tray 22 may then be lowered and plate 100 removed.
  • the amount of movement of mount 30 may be controlled to control the amount of liquids dispensed. As such, mount 30 need not be moved until stops 56 engage center plate 40.
  • system 10 may be employed to dispense liquids into wells which are either empty or partially filled with another liquid. For instance, in some cases, it may be advantageous to dispense into partially filled wells since this increases the level of precision.
  • tray 22 may be raised until the liquid droplets contact the bottom of the wells. When tray 22 is lowered, the liquid droplets adhere to the bottom of the wells, thereby transferring the liquid from the needles and into the wells.
  • System 10 is useful with a wide variety of liquids.
  • liquids such as DMSO, aqueous solvents, and the like may be utilized with system 10.
  • the syringes are constructed of stainless steel and are generally inert to a wide variety of chemicals, system 10 may be used in connection with a variety of chemical processes.
  • EXAMPLE A fluid dispensing system which is constructed essentially identical to system 10 of Fig. 1 was employed to dispense a liquid into the wells of an 864 well plate.
  • the wells of the plate were pre-filled with about 10 ⁇ l of a buffer solution.
  • the type of liquid aspirated into each of the needles was a fluorocine dye.
  • Sliding mount 30 was lowered to dispense about 2 ⁇ l of the dye into each well.
  • the maximum fluorescent count for any well was 218.77 and the minimum was 36.84.
  • the average was 166.75.
  • the standard deviation was 10.68 and the precision percentage was 6.40 percent CV.

Landscapes

  • Health & Medical Sciences (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)
  • Sampling And Sample Adjustment (AREA)
  • Devices For Use In Laboratory Experiments (AREA)
  • Feeding, Discharge, Calcimining, Fusing, And Gas-Generation Devices (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)

Abstract

L'invention porte sur des systèmes et procédés de transfert de liquides dont l'un comporte une base (12) et au moins 864 pipettes fonctionnellement reliées à la base (12). Chacune des pipettes comporte un embout distal pouvant aspirer ou éjecter un volume sensiblement égal de liquide. De plus, les embouts sont disposés à l'intérieur d'une surface de moins de 80 cm2.
EP00911980A 1999-03-01 2000-02-25 Systeme de transfert de liquides et procede associe Withdrawn EP1165234A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US26036899A 1999-03-01 1999-03-01
US260368 1999-03-01
PCT/US2000/004836 WO2000051735A1 (fr) 1999-03-01 2000-02-25 Systeme de transfert de liquides et procede associe

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EP1165234A1 true EP1165234A1 (fr) 2002-01-02

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EP (1) EP1165234A1 (fr)
JP (1) JP2002537978A (fr)
AU (1) AU3378600A (fr)
CA (1) CA2364012A1 (fr)
WO (1) WO2000051735A1 (fr)

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US20020151040A1 (en) 2000-02-18 2002-10-17 Matthew O' Keefe Apparatus and methods for parallel processing of microvolume liquid reactions
US20100261159A1 (en) 2000-10-10 2010-10-14 Robert Hess Apparatus for assay, synthesis and storage, and methods of manufacture, use, and manipulation thereof
WO2002030561A2 (fr) 2000-10-10 2002-04-18 Biotrove, Inc. Dispositifs d'essai biologique, de synthese et de stockage, et procedes de fabrication, d'utilisation et de manipulation de tels dispositifs
CA2521999A1 (fr) 2002-12-20 2004-09-02 Biotrove, Inc. Appareil et procede de dosage utilisant des reseaux microfluidiques
US8105554B2 (en) 2004-03-12 2012-01-31 Life Technologies Corporation Nanoliter array loading
US20060105453A1 (en) 2004-09-09 2006-05-18 Brenan Colin J Coating process for microfluidic sample arrays
CN103920425B (zh) * 2014-04-28 2016-03-02 四川沃文特生物技术有限公司 保证试剂加注准确性的系统
CN103920426B (zh) * 2014-04-28 2016-01-20 四川沃文特生物技术有限公司 对试剂管加注药液的装置
US20160346783A1 (en) * 2015-05-28 2016-12-01 Mo Bio Laboratories, Inc. Adjustable device for multi-channel pipette
WO2017119097A1 (fr) * 2016-01-07 2017-07-13 株式会社 エー・アンド・デイ Pipette multicanal
WO2018075577A1 (fr) * 2016-10-18 2018-04-26 President And Fellows Of Harvard College Procédés de traitement microfluidique intégré pour empêcher une perte d'échantillon

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AU3378600A (en) 2000-09-21
CA2364012A1 (fr) 2000-09-08
JP2002537978A (ja) 2002-11-12
WO2000051735A1 (fr) 2000-09-08

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