WO2002064812A2 - Distribution de microreseaux a haute capacite - Google Patents

Distribution de microreseaux a haute capacite Download PDF

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Publication number
WO2002064812A2
WO2002064812A2 PCT/US2001/045446 US0145446W WO02064812A2 WO 2002064812 A2 WO2002064812 A2 WO 2002064812A2 US 0145446 W US0145446 W US 0145446W WO 02064812 A2 WO02064812 A2 WO 02064812A2
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WO
WIPO (PCT)
Prior art keywords
microarrayer
slide
microplate
dispense
microplates
Prior art date
Application number
PCT/US2001/045446
Other languages
English (en)
Other versions
WO2002064812A3 (fr
Inventor
Brian L. Ganz
Mandel W. Mickley
John Andrew Moulds
Christopher T. Brovold
Original Assignee
Robodesign International, 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 Robodesign International, Inc. filed Critical Robodesign International, Inc.
Priority to EP01270118A priority Critical patent/EP1337337A2/fr
Priority to AU2002253796A priority patent/AU2002253796A1/en
Publication of WO2002064812A2 publication Critical patent/WO2002064812A2/fr
Publication of WO2002064812A3 publication Critical patent/WO2002064812A3/fr

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00279—Features relating to reactor vessels
    • B01J2219/00306—Reactor vessels in a multiple arrangement
    • B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
    • B01J2219/00315—Microtiter plates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00351—Means for dispensing and evacuation of reagents
    • B01J2219/00387—Applications using probes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00497—Features relating to the solid phase supports
    • B01J2219/00527—Sheets
    • 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
    • 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
    • B01J2219/0059—Sequential processes
    • 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
    • B01J2219/00596—Solid-phase processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B01J2219/00612—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports the surface being inorganic
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00659—Two-dimensional arrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00677—Ex-situ synthesis followed by deposition on the substrate
    • 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
    • B01J2219/0068—Means for controlling the apparatus of the process
    • B01J2219/00686—Automatic
    • B01J2219/00689—Automatic using computers
    • 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
    • B01J2219/0068—Means for controlling the apparatus of the process
    • B01J2219/00686—Automatic
    • B01J2219/00691—Automatic using robots
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/02—Burettes; Pipettes
    • B01L3/0241—Drop counters; Drop formers
    • 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
    • G01N35/00029—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor provided with flat sample substrates, e.g. slides
    • G01N2035/00099—Characterised by type of test elements
    • G01N2035/00158—Elements containing microarrays, i.e. "biochip"
    • 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
    • G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations
    • G01N35/04—Details of the conveyor system
    • G01N2035/0401—Sample carriers, cuvettes or reaction vessels
    • G01N2035/0418—Plate elements with several rows of samples
    • G01N2035/0422—Plate elements with several rows of samples carried on a linear conveyor

Definitions

  • the present invention relates to automated microarray dispensing devices, more specifically it relates to high capacity automated microarray dispensing devices.
  • Microarrays also known as biochips, have recently become important in the study of genomics.
  • the use of a microarray involves laying down an ordered array of genetic elements onto a solid substrate such as a slide.
  • a microarray may consist of genomic DNA, reverse-transcribed cDNA, or smaller chains of oligonucleotides as well as any preparatory substrates.
  • the microarray is useful because it allows genetic analysis to take place on a massively parallel scale, wherein thousands of genes and markers can be scored in one experiment.
  • a microplate is a plate that may contain samples of genetic material in solution in small wells.
  • a microarrayer also known as a DNA array printer, is a high-capacity system used to print a microarray onto slides.
  • a microarrayer is a specially built robotic platform designed to transfer solutions from the well of some type of microplate onto another surface for analysis. This process of depositing the liquid spot onto the slide is known as "spotting".
  • microarrayers have become extremely popular in laboratories because they add to the efficient productivity of the laboratory to be able to print samples onto slides accurately and rapidly.
  • Affymetrix, Inc. with offices in Santa Clara, California, makes an automated arrayer called the 417 ARRAYER (Part No. 0-0001 and Part No. 0-0009).
  • BioRobotics with offices in Boston, Massachusetts, produces two versions of an automated arrayer called the MICROGRID and M1CROGRID II.
  • GeneMachines with offices in Menlo Park, California, makes an arrayer called the OMNIGRID (Model No. OGR-02). Packard Instrument Company with offices in Meriden, Connecticut makes an automated arrayer called the BIOCHIP ARRAYER.
  • BIOCHIP ARRAYER made by Packard Instrument Company has attempted to deal with the problem of monitoring the spotting process. However, it has only limited verification functionality with its integrated camera. This means that it verifies whether or not a spot has been dispensed, without any quality inspection to analyze whether that spot was good or bad.
  • the present invention provides a high capacity microarrayer for spotting solution onto slides in an automated microarray dispensing device.
  • a microplate indexing device automatically moves, in sequence, a plurality of microplates to a solution removal area.
  • a dispense head accesses each microplate at the solution removal area to remove solution from the microplate.
  • the dispense head then moves to a slide positioning station to spot slides at the slide positioning station.
  • the microplate indexing station has at least one input stacking chamber for stacking microplates, and at least one output stacking chamber for stacking microplates.
  • a walking beam indexer is disposed between the at least one input stacking chamber and the at least one output stacking chamber.
  • the walking beam indexer is for moving microplates from said at least one input stacking chamber to said at least one output stacking chamber. While at the solution removal area, a lid lifter lifts the lid off each microplate to permit the microplate to be accessed by the dispense head for solution removal. After the solution is removed, the lid lifter replaces the lid.
  • the at least one camera is capable of acquiring and transmitting slide image data to a computer.
  • the computer is programmed to receive the slide image and analyze it. The computer will then generate post analysis data based on the analysis of the slide image data.
  • the post analysis data is available for improving the spotting of the solution onto the slides.
  • the slide image data includes information relating to slide alignment, information relating to spot quality, and slide identification information.
  • the analysis of the information relating to slide alignment enables the computer to make automatic adjustments to the relative positions of the at least one dispense head and the slides to increase the accuracy of the spotting.
  • the analysis of the information relating to spot quality identifies a spot as pass or fail. An operator is then able to rework the spot.
  • the analysis of the slide identification information enables the computer to track each slide.
  • FIG. 1 shows the major components of a preferred embodiment of the present invention.
  • FIG. 2 shows slides fifty slides located on 5 locating plates after the slides have been spotted.
  • FIGS. 3 - 32 illustrate the sequence of operation of a preferred embodiment of the present invention.
  • FIG. 33 shows the major components of a preferred embodiment of the present invention.
  • FIG. 34A shows the rework dispense head in the up position.
  • FIG. 34B shows the rework dispense head in the down position.
  • FIG. 34C shows a slide with a 2D bar code.
  • FIGS. 35A and 35B shows dispense tips attached to dispense heads.
  • FIG. 36 shows a preferred embodiment of the present invention mounted on a vibration isolated base.
  • FIG. 37 shows the major components of a preferred embodiment of the present invention.
  • FIGS. 38A and 38B show a flowchart for the programming of a preferred embodiment of the present invention.
  • FIGS. 39A and 39B show the reworking of a slide for a preferred embodiment of the present invention.
  • FIG. 40 shows another preferred embodiment of the present invention.
  • FIG. 41 shows another preferred embodiment of the present invention.
  • FIG. 42 shows a third preferred embodiment of the present invention.
  • FIGS. 43A - 43D show a sequence of operation of the third preferred embodiment.
  • FIGS. 44 A - 44B show the microplate indexing station.
  • FIGS. 45 - 76 show a detailed sequence of operation of the third preferred embodiment.
  • FIG. 77 shows a top view of a microplate.
  • FIGS. 78A - 78E show slides.
  • FIGS. 79 - 86 show a detailed sequence of operation of the third preferred embodiment.
  • FIG. 87 shows a detailed view of the input singulator.
  • FIGS. 88 and 89 show some major components of the third preferred embodiment.
  • FIG. 90 shows a detailed perspective view of a preferred output chamber.
  • FIG. 92 shows a detailed side view of a preferred output chamber.
  • FIGS. 92 - 95 show a sequence illustrating a preferred method for stacking microplates in the output chamber.
  • solution from reservoir plate 5 is automatically deposited onto an array of fifty blank slides 4A1 - 4E10 located on locating plates 4A - 4E (see FIG. 1).
  • An operator is able to select via a computer interface whether dispense tip 42 (located underneath dispense head 40) or a 4 x 6 array of dispense tips 7 (located underneath dispense head 6) will be used to make the deposits onto slides 4A1 - 4E10.
  • dispense tips 7 and 42 are quill type dispense tips.
  • Locating plates 4A - 4E are mounted on linear actuator 15 so that they can move along the x- axis.
  • Linear actuator 26 is mounted on linear actuator 21 so that linear actuator 26 can move along the y-axis.
  • Dispense heads 6 and 40 are mounted on linear actuator 26 so that they can move along the z-axis.
  • Camera 12 with strobe light 13 is focused so as to permit recording of the deposition process and functions to permit verification of slide identification information and to permit verification of proper deposition of solution on the slides.
  • the dispense tips are cleaned in sonic cleaner 9, rinsed in rinse fountain 10, and then dried in vacuum manifold 11. After the solution has been deposited onto the slides, the operator can retrieve locating plates 4 A - 4E containing slides 4A1 - 4E10 from the position shown in FIG. 2.
  • FIGS. 3 - 32 illustrate the sequence of operation of a preferred embodiment of the present invention.
  • FIGS. 38A - 38E show a flowchart representing preferred programming of PC control system 300 and corresponds to the sequence illustrated in FIGS. 3 - 32.
  • slides 4A1 - 4E10 are made by Sequonem with offices in San Diego, CA.
  • a preferred slide is shown in FIG. 16B. It has ninety-six etched dispense positions 60 and has its own unique 2D bar code 65 for identification purposes.
  • linear actuator 15 moves platform 2 so that slide 4A1 is underneath the dispense head 6.
  • Dispense head 6 is positioned directly above slide 4A1.
  • camera 12 and the strobe light 13 an image is acquired of slide 4A1.
  • the camera reads the bar code and inspects the positioning and alignment of slide 4A1 on locating plate 3A.
  • the software then analyzes the position data and stores the information. The information stored and will be used later to adjust the positions of slide 4A1 and dispense head 6 to ensure accurate placement of the solution on the slide.
  • linear actuator 26 is moved via linear actuator 21 to the position shown in FIG. 5 so that dispense head 6 is directly above slide 4A2.
  • camera 12 and the strobe light 13 an image is acquired of slide 4A2.
  • camera reads the bar code and inspects the positioning and alignment of slide 4A2 on locating plate 4A.
  • the software analyzes the position data and stores the information. The information stored and will be used later to adjust the positions of slide 4A2 and dispense head 6 to ensure accurate placement of the solution on the slide.
  • Linear actuator 26 is then moved via linear actuator 21 to the position shown in FIG. 6 so that dispense head 6 is directly above sonic cleaner 9.
  • mounting plate 25 moves downward via linear actuator 26 so that dispense tips 7 are dipped in sonic cleaner 9 for a programmable time period while the cleaner is turned on. When finished, mounting plate 25 moves upward as shown in FIG. 8.
  • platform 31 moves to the left via pneumatic slide 30, thereby moving rinse fountain 10 and vacuum manifold 11 to the left.
  • Linear actuator 26 is moved via linear actuator 21 back so that it is directly above rinse fountain 10.
  • mounting plate 25 moves downward via linear actuator 26 so that tips 7 are dipped in rinse fountain 10 for a programmable time period while the fountain is turned on.
  • mounting plate 25 moves upward via linear actuator 26, as shown in FIG. 11.
  • Platform 31 moves to the right via pneumatic slide 30, thereby moving rinse fountain 10 and vacuum manifold 11 to the right.
  • dispense tips 7 are then lowered into the vacuum manifold 11 via linear actuator 26 and the vacuum is turned on for a programmable time period, thereby drying dispense tips 7.
  • This cleaning cycle can be set by the user, via the computer interface, to be repeated as many times as necessary.
  • Mounting plate 25 is then raised via linear actuator 26 as shown in FIG. 13.
  • Linear actuator 26 is then moved via linear actuator 21 so that dispense head 6 is directly above reservoir plate 5, as shown in FIG. 14.
  • Mounting plate 25 is then lowered via linear actuator 26 so that tips 7 are dipped into the solution contained in reservoir plate 5, as shown in FIG. 15. While in reservoir plate 5, dispense tips 7 pick up some of the solution to be dispensed.
  • Linear actuator 26 then moves to the first dispense position shown in FIG. 16A so that dispense head 6 is above slide 4A1. Based on the earlier positioning data regarding slide 4A1 (see discussion of FIG. 4), linear actuator 21 makes minute positioning adjustments to linear actuator 26 and linear actuator 15 makes minute positioning adjustments to platform 2 in order to accurately position dispense head 6 over slide 4A1 at the first dispense position.
  • FIG. 16B shows a top view of a blank slide 4A1.
  • slide 4A1 has 96 positions 60 arranged in an 8 x 12 array. At each position 60, slide 4A1 is etched so as to be better able to retain a drop of solution deposited at the spot.
  • Dispense head 6 is then lowered via linear actuator 26 so that tips 7 are in contact with slide 4A1 at the first dispense position, as shown in FIG. 17 A.
  • spots 62 are placed on slide 4A1 via surface tension, as shown in FIG. 17B.
  • Dispense head 6 is raised via linear actuator 26, as shown in FIG. 18. Based on the earlier positioning data regarding slide 4A1, linear actuator 21 makes minute positioning adjustments to linear actuator 26 and linear actuator 15 makes minute positioning adjustments to platform 2 in order to accurately position dispense head 6 over slide 4A1 at the second dispense position. Dispense head 6 is then lowered via linear actuator 26 so that tips 7 are in contact with slide 4A1 at the second dispense position, as shown in FIG. 19A. As tips 7 contact slide 4A1, more spots 62 are added to slide 4A1, as shown in FIG. 19B.
  • Dispense head 6 is raised via linear actuator 26, as shown in FIG. 20.
  • linear actuator 21 makes minute positioning adjustments to linear actuator 26 and linear actuator 15 makes minute positioning adjustments to platform 2 in order to accurately position dispense head 6 over slide 4A1 at the third dispense position.
  • Dispense head 6 is then lowered via linear actuator 26 so that tips 7 are in contact with slide 4A1 at the third dispense position, as shown in FIG. 21 A. As tips 7 contact slide 4A1, more liquid spots 62 are added to slide 4A1, as shown in FIG. 21B.
  • Dispense head 6 is raised via linear actuator 26, as shown in FIG. 22.
  • linear actuator 21 makes minute positioning adjustments to linear actuator 26 and linear actuator 15 makes minute positioning adjustments to platform 2 in order to accurately position dispense head 6 over slide 4A1 at the fourth dispense position.
  • Dispense head 6 is then lowered via linear actuator 26 so that tips 7 are in contact with slide 4A1 at the fourth dispense position, as shown in FIG. 23A. As tips 7 contact slide 4A1, more liquid spots 62 are added to slide 4A1, as shown in FIG. 23B.
  • Dispense head 6 is raised via linear actuator 26, as shown in FIG. 24.
  • Camera 12 and strobe 13 scans slide 4A1 and acquires images and inspects for spot quality. It is at this point that PC control system 300 (FIG. 37) identifies slide 4A1 as pass or fail. (Preferred computer controlled techniques for making this determination are discussed in a following section.)
  • linear actuator 21 makes positioning adjustments to linear actuator 26 and linear actuator 15 makes positioning adjustments to platform 2 in order to accurately position dispense head 6 over slide 4A2 at the first dispense position for slide 4A2.
  • the four-stage liquid dispense cycle (explained above with respect to slide 4A1 in discussion regarding FIGS. 17A - 24) is repeated so that at the end of the four- stage cycle, slide 4A2 contains spots 62, as shown in FIG. 26B.
  • dispense head 6 is raised via linear actuator 26, as shown in FIG. 26A.
  • Camera 12 and strobe 13 scans slide 4A2 and acquires images and inspects for spot quality. It is at this point that the control system identifies slide 4A2 as pass or fail.
  • linear actuator 21 moves linear actuator 26 so that dispense head 6 is above slide 4A3.
  • slides 4A1 and 4A2 are repeated with regards to slides 4A3 and 4A4.
  • camera 12 will first record the positions of slides 4A3 and 4A4.
  • dispense tips 7 are dipped in sonic cleaner 9.
  • Dispense tips 7 are then rinsed in rinse fountain 10.
  • dispense tips 7 are dried in vacuum manifold 11. This cycle is repeated as needed.
  • liquid is picked up by dispense tips 7 when dispense tips 7 are lowered into reservoir plate 5.
  • liquid is spotted onto slide 4A3 by dispense tips 7 in a four-stage liquid dispense cycle.
  • liquid is spotted onto slide 4A4 in a four-stage liquid dispense cycle so that liquid has been spotted on both slides, as shown in FIGS. 28B and 28C.
  • Linear actuator 15 then moves platform 2 so that slide 4B1 of locator plate 4B is underneath dispense head 6, as shown in FIG. 30.
  • dispense tips 7 continue to spot all ten slides on locator plates 4B - 4E, until the last slide 4E10 has been spotted, as shown in FIG. 31.
  • linear actuator 15 moves platform 2 to the position shown in FIG. 32 so an operator can remove locator plates 4A - 4E.
  • the computer controlled pass-fail determination technique determines individual spots as pass or fail based on several criteria. For each slide, the camera system scans a region to look for a spot.
  • the criteria that are applied to that inspection region are spot presence, spot size in area, spot location, and spot geometry. Additional criteria can be added through software configuration. Each of the criteria can have upper and lower limits designated which define the acceptable values for that particular criteria. Any value that falls outside of the limits for any criteria qualifies that spot and slide as failed.
  • the actual inspection values are determined by analyzing the grayscale intensity of each pixel. The total number of pixels falling above and below a threshold are tallied to give values for each of the inspection criteria.
  • FIG. 29 shows locating plate 4A after all slides 4A1 - 4A10 have been spotted.
  • an operator can scan locating plate 4A.
  • a good plate shows up green as in all slides pass.
  • a plate with at least one bad spot on one of the slides shows up red.
  • the user can then zoom in on the bad slide and the good and bad spots show up green and red respectively as pass or fail. From there, the user can decide whether or not to rework the bad spots.
  • FIGS. 39A and 39B show where an operator has decided to rework slide 4A6 that has a spot that has failed quality inspection.
  • Dispense head 40 is lowered via pneumatic slide 41 so that dispense tip 42 is lower than dispense tips 7.
  • Solution from reservoir plate 5 is then deposited on the slide at the location of the failed spot. If there are other spots that failed, the operator can likewise rework those spots in a similar fashion.
  • the computer makes a determination whether or not a spot has passed or failed using the computer controlled pass-fail determination technique earlier described. If, based on its analysis, the computer determines that the spot has failed, the computer will automatically take steps to rework the spot. For example, dispense tip 42 will extract solution from reservoir plate 5. Then, the computer will lower dispense head 40 via pneumatic slide 41 so that dispense tip 42 is lower than dispense tips 7, as shown in FIGS. 39A and 39B. Solution from reservoir plate 5 will then deposited on the slide at the location of the failed spot.
  • linear actuators 26, 21 and 15 are industrial grade precision ground ball screw linear actuators, as shown in FIG. 33. These linear actuators are manufactured by Parker Automation ( Model #s:404XR and 406XR series). They are each controlled by a smart servomotor (SmartMotor, Model #2320 VRE, manufactured by Animatics, with offices in Santa Clara CA), which is a fully self-contained closed loop servo system. Each of these smart servomotors contains the motor, encoder, amplifier, and controller all in one small package mounted to the linear actuator.
  • Linear actuator 15 (the x-axis positioning device) has an overall travel distance of 600 mm with an accuracy within +/- 0.032 micrometers
  • Linear actuator 21 (the y-axis positioning device) has an overall travel distance of 400 mm with an accuracy within +/- 0.032 micrometers.
  • Linear actuator 26 (the z-axis positioning device) has an overall travel distance of 100 mm with an accuracy within +/- micrometers. In this preferred embodiment, this extreme accuracy is needed to accommodate very small spot size and spacing between spots.
  • the linear actuators have pitches of 5mm per revoloution giving a positioning accuracy of 0.032 x IO "6 meters.
  • Linear actuator 15 controls the positioning of platform 2 containing slides 4A1 - 4E10 along the x-axis of motion making all slides presentable to the dispense head 6.
  • Linear actuator 21 controls the positioning of the dispense head along the y-axis of motion making all slides 4A1 - 4E10, sonic cleaner 9, rinse fountain 10, vacuum manifold 11 , and reservoir plate 5 presentable to dispense head 6.
  • Linear actuator 26 controls the positioning of dispense head 6 along the z-axis of motion allowing dispense head 6 to be lowered to and raised from all slides 4A1 - 4E10, sonic cleaner 9, rinse fountain 10, vacuum manifold 11, and reservoir plate 5.
  • sonic cleaner 9 is an ultrasonic cleaner manufactured by Prosonic, Inc. (part no. E0028). Sonic cleaner 9 can contain either a cleaning solution or simply purified water. Dispense tips 7 are dipped in the sonic cleaner 9, where the ultra sonic oscillations of the cleaning solution clean the tips.
  • Rinsing fountain 10 and the vacuum manifold 11 are placed on a pneumatic slide 30.
  • Pneumatic slide 30 is used to select which operation is to be performed, rinsing or drying. The reason for this slide is so that both operations can be performed at a single position along the y-axis. This allows for both operations without having to increase the overall travel of linear actuator 26 along the y-axis.
  • Rinsing fountain 10 pumps in purified water and drains it out to a waste bin. Dispense tips 7 are dipped in this purified water to rinse away any debris or cleaning solution that may remain on the tips after cleaning.
  • Drying vacuum manifold 11 is a block with an array of holes in it that match the array of dispense tips 7. The tips are inserted into the block, each of these holes are connected to a manifold which is connected to a vacuum generator and air supply. The vacuum pulls away any remaining liquid or debris left on the dispense tips after rinsing.
  • dispense head 6 is a 4 x 6 grid Micro Quill Holder (part no. 11946-0) made by Major Precision of Arizona.
  • a 4 x 6 array of primary dispense tips 7 are held in dispense head 6.
  • dispense head 40 is a Micro Quill Holder also made by Major Precision.
  • Dispense tip 42 is held in dispense head 40.
  • Dispense tips 7 and 42 are spring loaded within the dispense heads 6 and 40.
  • dispense head 6 is rigidly mounted to mounting plate 25, whereas dispense head 40 is mounted to pneumatic slide 41 (manufactured by Robohand, Inc., with offices in Montroe, CT, part no. MPS1-2).
  • Mounting plate 25 is capable of moving up and down along the z-axis via linear actuator 26.
  • dispense head 40 is capable of independent additional movement up and down along the z-axis via pneumatic slide 41, as shown in FIGS. 34A - 34B.
  • FIG. 34C shows a front view of dispense tips 7 in contact with slide 4A1. Dispense tips 7 will be used to spot slide 4A1 at positions 60, as shown in FIG. 34C. Note that when dispense head 6 has been selected, dispense head 40 is raised via pneumatic slide 41 so that dispense tips 42 do not interfere with the spotting process. If, however, the operator wishes to spot slide 4A1 at positions 61 (FIG. 34C), dispense head 40 will be lowered via pneumatic slide 41 so that dispense tips 42 are in contact with slide 4A1 and dispense tips 7 are out of the way, as shown in FIG. 34B.
  • camera 12 and strobe 13 are mounted to the side of linear actuator 26 as shown in FIG. 1.
  • Camera 12 is a self-contained camera with image processing and Ethernet capabilities manufactured by DVT Corporation with offices in Norcross, GA (series 600 model).
  • strobe 13 can snap pictures while in dynamic motion, process the image for results, pass the results off to the PC control system, and prepare for the next image acquisition.
  • the camera uses a 55 mm Telecentric lens which provides the proper field of view and magnification for reading of 2D bar code 62 (FIG. 34C) and for image inspection.
  • Strobe light 13 is preferably Model DL2449, manufactured by Advanced Illumination, with offices in Rochester, VT.
  • the image acquisition time is ⁇ 40 ms and the image processing time is ⁇ 50 ms.
  • the system can also be equipped with a flouresence device along with the camera for further genomic expression analysis.
  • Vibration Isolated Base 80 is provided to minimize any possible affects that high frequency environmental vibrations might have on the dispensing process.
  • This base is a pneumatic system which acts as a shock absorber to the system.
  • the base is manufactured by Newport, Inc. with offices in Irvine, CA, model # CM-225.
  • FIG. 37 depicts a block diagram of PC control system 300 and other components of a preferred embodiment of the present invention.
  • PC Control System 300 includes CPU 301 with associated memory (RAM 302 and ROM 303). It also includes a touch screen monitor/interface 305 that allows for operator monitoring, intervention and control of the present invention.
  • the computer system is a PC based computer equipped with an ethernet card and running windows software. The programming is preferably written in VISUAL BASIC. (VISUAL BASIC is a federally registered trademark of Microsoft Corp., a Delaware Corporation)
  • PC Control System 300 is equipped with CMS (Central Monitoring System). The CMS gives PC Control System 300 it's own IP (Internet Protocol) address and ethernet connectivity.
  • IP Internet Protocol
  • the software is highly comfigurable to allow increased flexibility for customers with varying slide types, slide sizes, slide orientations, spot size, spot spacing and many other variables.
  • linear actuators 26, 21 and 15 are industrial grade precision ground ball screw linear actuators.
  • PC control system 300 sends signals to smart servomotors 26A, 21 A and 15A to control linear actuators 26, 21 and 15, respectively.
  • PC control system 300 controls sonic cleaner 9 and rinse fountain 10.
  • Compressed air source 310 provides compressed air to pneumatic slides 30 and 41 via valves 310 controlled by PC control system 300.
  • Vacuum generator 320 provides a vacuum to vacuum manifold 1 1 via valve 317.
  • camera 12 and strobe 13 work in conjunction to provide sensory data to PC control system 300.
  • This input is used to accurately position the dispense heads over the slides to ensure optimum spotting and to verify the quality of the spotting as "pass” or “fail” using multiple criteria as to placement at intended location as well as spot size (too big or too small).
  • FIG. 41 A second preferred embodiment of the present invention is shown in FIG. 41.
  • dispense head 106 is connected via mounting plate 125 to linear actuator 126 so that dispense tips 107 can be raised and lowered along the z- axis into solution in microplate 190.
  • Camera 112 and strobe 113 are rigidly mounted to the side of linear actuator 126 so that they remain stationary with respect to the side of linear actuator 126 along the z-axis.
  • Linear actuator 126 is mounted to linear actuator 121 so that it can move along the y-axis.
  • Platform 182 is mounted to linear actuator 180 so that it can move along the x-axis.
  • Locating plate 4A is placed on top of platform 182.
  • Platform 102 is mounted to linear actuator 115 so that it can move along the x-axis.
  • Microplate 190 is place on top of platform 102. In this preferred embodiment platform 102 has the capacity to hold ten microplates 190.
  • Solution in microplate 190 is removed via dispense tips 107.
  • Linear actuator 126 then moves along the y-axis so that dispense tips 107 are above locating plate 4A.
  • the solution is then spotted in a fashion similar to that described for the earlier preferred embodiments.
  • Camera 112 with strobe 113 is focused so as to permit recording of the deposition process and functions to permit verification of slide identification information, permit verification of proper deposition of solution on the slides, and to verify slide alignment.
  • slide image data is transferred via camera 112 to a PC control system where the data is analyzed. The results of the analysis are then available for improving the spotting of the solution onto the slides. For example, spots that have failed to meet the threshold limits can be reworked.
  • the computer can automatically make adjustments to the relative positions of the slides and dispense tips based on the slide alignment analysis. Periodically, during the cycle, the dispense tips are cleaned in sonic cleaner 109, then rinsed in the rinse fountain and dried in vacuum manifold 111.
  • Second Preferred Embodiment has High Capacity Capability
  • ten different microplates can be positioned on platform 102.
  • Platform 102 is mounted on linear actuator 115.
  • Linear Actuator 115 can move platform 102 and any microplates mounted on platform 102 so that any particular microplate is directly below dispense tips 107.
  • the area below dispense tips 102 constitutes a solution removal area.
  • One of ordinary skill in the art will recognize that by making platform 102 larger, the number of solution filled microplates positioned on platform 102 can be increased, thereby increasing the overall capacity of the second embodiment.
  • the first preferred embodiment (described in the sequence illustrated in FIGS 3 - 32) can be used in conjunction with the second preferred embodiment to spot slides.
  • locating plate 4A can be removed from the microarrayer via an operator after it has been spotted with a base solution. Locating plate 4A can be transferred to the microarrayer depicted in FIG. 41. It can be placed on platform 180. DNA from microplate 190 can then be spotted on top of the base solution spotted already on slides 4A1 - 4A10.
  • FIG. 42 A perspective view of the third preferred embodiment is seen by reference to FIG. 42.
  • the third preferred embodiment is similar to the second preferred embodiment in that it has the advantage of accommodating high capacity microplate handling capabilities.
  • the third preferred embodiment of the present invention utilizes microplate indexing station 700, also shown in FIGS. 44A and 44B.
  • Embodiments of microplate indexing station 700 were described in detail in U.S. App. No. 09/411 ,943, the specification of which is herein incorporated by reference.
  • microplate indexing station 700 was described as being used in conjunction with an automated microplate filling device and it included a microplate fill nozzle.
  • microplate indexing station 700 is used in conjunction with other components to dispense solution onto slides.
  • solution filled microplates are stacked inside input chamber 500 of microplate indexing station 700, as shown in FIG. 42. They are then sequentially moved towards output chamber 502 via walking beam indexer 37. When a microplate reaches position ⁇ , its lid is removed via lid lifter 44.
  • FIG. 44B shows a top view of microplate indexing station 700 with microplates at five different positions ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ .
  • Lid lifter 44 then moves the microplate lid out of the way via lid lifter retractor 750 (FIG. 44 A, 44B, 67 - 68).
  • Solution can then be extracted from the microplate via dispense tips 7 mounted on dispense head 6.
  • the solution is then deposited on slides located at slide station 702.
  • its lid is replaced via lid lifter 44 and the microplates are sequentially stacked inside output chamber 502.
  • dispense head 6 is moved back and forth between microplate indexing station 700 and slide station 702 via linear actuator 21. Slides at slide station 702 are moved from left to right via linear actuator 15.
  • dispensing tips 7 FIG.
  • FIGS. 42 and 43A an operator places four locating plates 40A - 40D each having ten clean, blank slides 40 A 1 - 40D10 on platform 2.
  • a preferred slide is shown in FIG. 78A. It has ninety-six etched dispense positions 60 and has its own unique 2D bar code 65 for identification purposes.
  • microplates 601 - 620 are each 384-well microplates.
  • FIG. 89 shows the major components associated with microplate indexing station 700.
  • PLC 300 automatically conducts a start up routine. In this routine, PLC 300 checks all PLC 300 controlled components, homes all pneumatic devices and checks all sensors. If there are any errors (for example, jammed microplates or component malfunction), the user will be alerted via monitor 305.
  • PLC 300 checks all PLC 300 controlled components, homes all pneumatic devices and checks all sensors. If there are any errors (for example, jammed microplates or component malfunction), the user will be alerted via monitor 305.
  • microplates 601 - 620 are 384-well microplates.
  • PLC 300 selects walking beam indexer 37 positioning data.
  • FIG. 45 shows a stack of twenty filled microplates 601 - 620 loaded into input chamber 500.
  • Microplate 601 is at the bottom at position (FIG. 44B) and microplate 602 is directly above microplate 601.
  • Microplate 620 is at the top of the stack.
  • output stack 502 is empty with no microplates.
  • walking beam indexer 37 is lowered via pneumatic cylinders 52 so that dowel pins 14 are below the horizontal plane formed by the top surface of beam 8.
  • input chamber singulator 23 has lifted input stack 602 - 620 at microplate 602.
  • Microplate 601 is left at position ⁇ , as shown in FIG. 44B.
  • a detailed view of input chamber singulator 23 lifting input stack 602 - 620 is seen in FIG. 87.
  • Input chamber singulator 23 was described in detail in U.S. patent application serial no. 09/441,943).
  • Input chamber singulator 23 lifts microplate 602 allowing a small gap to form between microplate 601 and 602. Since input stack 602 - 620 is confined on all sides by input chamber 500, instead of tilting input stack 602 - 620, lifting from the front edge lifts the entire stack vertically. Also, as shown in FIG. 47, walking beam indexer 37 has moved to the right.
  • walking beam indexer 37 is raised so that dowel pin 14 is located directly behind microplate 601.
  • walking beam indexer 37 has moved to the left pushing microplate 601 to position ⁇ (see FIG. 4) from the bottom of the stack. As soon as microplate 601 is no longer above input chamber lifter 802, input chamber lifter 802 moves upward so that it is supporting input stack 602 -620 along with input chamber singulator 23.
  • walking beam indexer 37 has been lowered so that dowel pins 14 are below the horizontal plane formed by the top surface of beam 8.
  • Input chamber singulator 23 and input chamber lifter 802 has lowered the input stack.
  • Microplate 601 is at position ⁇ and microplate 602 is at position ⁇ .
  • walking beam indexer 37 has moved to the right.
  • Input chamber singulator 23 has lifted input stack 603 - 620, leaving behind microplate 602 at position ⁇ .
  • walking beam indexer 37 is raised so that dowel pin 14 is located directly behind microplate 602.
  • lid lifter 44 has dropped to the top of microplate lid 27 of microplate 601 and has grasped microplate lid 27 with a vacuum force via lid lifter vacuum cups 4 IB.
  • lid lifter 44 has lifted microplate lid 27.
  • Microplate 601 is at position ⁇ (see FIG. 44B) and microplate 602 is at position ⁇ .
  • the side view shown in FIG. 55 corresponds to the top view shown in FIG. 67.
  • lid lifter 44 via lid lifter retractor 750, has moved microplate lid 27 out of the way so that it is no longer directly above microplate 601.
  • FIG. 61 is a top view of the present invention and corresponds with the perspective drawing shown in FIG. 42.
  • linear actuator 15 moves platform 2 and linear actuator 21 moves linear actuator 26 so that dispense head 6 is positioned directly above slide 40A1.
  • camera 12 and the strobe light 13 an image is acquired of slide 40A1.
  • the camera reads the bar code and inspects the positioning and alignment of slide 40A1 on locating plate 40 A.
  • the software analyzes the position data and stores the information. The information stored and will be used later to adjust the positions of slide 40A1 and dispense head 6 to ensure accurate placement of the solution on the slide.
  • linear actuator 26 is moved via linear actuator 21 to the position shown in FIG. 63 so that dispense head 6 is directly above slide 40A2.
  • camera 12 and the strobe light 13 an image is acquired of slide 40 A2.
  • camera reads the bar code and inspects the positioning and alignment of slide 40A2 on locating plate 40A.
  • the software analyzes the position data and stores the information. The information stored and will be used later to adjust the positions of slide 40A2 and dispense head 6 to ensure accurate placement of the solution on the slide.
  • Linear actuator 26 is then moved via linear actuator 21 to the position shown in FIG.
  • Dispense tips 7 are dipped into sonic cleaner 9 and then raised. The procedure for dipping dispense tips 7 into sonic cleaner 9 is described in detail above.
  • Linear actuator 26 is then moved via linear actuator 21 to the position shown in FIG.
  • Dispense tips 7 are dipped into rinse fountain 10 and then raised. The procedure for dipping dispense tips 7 into rinse fountain 10 is also described in detail above.
  • Linear actuator 26 is then moved via linear actuator 21 to the position shown in FIG.
  • Dispense tips 7 are dipped into vacuum manifold 11 and then raised.
  • the procedure for dipping dispense tips 7 into vacuum manifold 1 1 is also described in detail above.
  • the cleaning cycle described in FIGS. 64 - 66 can be set by the user, via the computer interface, to be repeated as many times as necessary.
  • Mounting plate 25 is then lowered via linear actuator 26 so that tips 7 are dipped into microplate 601, as shown in FIG. 71. While in microplate 601 dispense tips 7 pick up some of the solution to be dispensed.
  • FIG. 77 An enlarged top view of microplate 601 is shown in FIG. 77.
  • solution is removed from the 4 x 6 array at first removal position 81.
  • Mounting plate 25 is then raised via linear actuator 26, as shown in FIG. 72.
  • Linear actuator 26 then moves so that dispense head 6 is above slide 40A1, as shown in FIG. 73. Based on the earlier positioning data regarding slide 40A1, linear actuator 21 makes minute positioning adjustments to linear actuator 26 and linear actuator 15 makes minute positioning adjustments to platform 2 in order to accurately position dispense head 6 over slide 40 A 1 at the first dispense position.
  • Dispense head 6 is then lowered via linear actuator 26 so that tips 7 are in contact with slide 40 A 1 at the first dispense position. As tips 7 contact slide 40 A 1 at the first dispense position, spots 62 are placed on slide 40 A 1 via surface tension, as shown in FIG. 78B.
  • Dispense head 6 is raised via linear actuator 26.
  • Linear actuator 26 is moved via linear actuator 21 so that it is above microplate 601 at position ⁇ (FIG. 44B), as shown in FIGS. 69 and 70. Then positioning adjustments are made to linear actuator 26 and to walking beam indexer 37 so that dispense head 6 is directly above microplate 601 at second removal position 82, as shown in FIG. 77.
  • Mounting plate 25 is then lowered via linear actuator 26 so that dispense tips 7 are dipped into microplate 601 at second removal position 82. While in microplate 601 dispense tips 7 pick up some of the solution to be dispensed.
  • Linear actuator 26 then moves so that it is positioned over slide 40A1. Based on the earlier positioning data regarding slide 40A1, linear actuator 21 makes minute positioning adjustments to linear actuator 26 and linear actuator 15 makes minute positioning adjustments to platform 2 in order to accurately position dispense head 6 over slide 40A1 at the second dispense position.
  • Dispense head 6 is then lowered via linear actuator 26 so that tips 7 are in contact with slide 40A1 at the second dispense position. As tips 7 contact slide 40A1 at the second dispense position, spots 62 are placed on slide 40 A 1 via surface tension, as shown in FIG. 78C.
  • Dispense head 6 is raised via linear actuator 26.
  • solution is removed from microplate 601 at third removal position 83 and then deposited on slide 40 A 1 at the third dispense position so that spots 62 are deposited as shown in FIG. 78D.
  • solution is removed from microplate 601 at fourth removal position 84 and deposited on slide 40A1 at the fourth dispense position so that spots 62 are deposited as shown in FIG. 78E.
  • Slide 40A1 as shown in FIG. 78E, has been completely spotted.
  • PC control system 300 (FIGS. 88 - 89) identifies slide 40A1 as pass or fail. (Preferred computer controlled techniques for making this determination were discussed in a preceding section.)
  • walking beam indexer 37 moves slightly to the right, as shown in FIG. 74.
  • Linear actuator 26 is moved via linear actuator 21 to a position above microplate 601 at position ⁇ (FIG. 44B). Then, positioning adjustments are made to linear actuator 26 and to walking beam indexer 37 so that dispense head 6 is directly above microplate 601 at fifth removal position 85, as shown in FIG. 77. Solution is then removed from fifth removal position 85.
  • linear actuator 26 is then moved so that it is above slide 40A2. Based on the earlier positioning data regarding slide 40A2, linear actuator 21 makes minute positioning adjustments to linear actuator 26 and linear actuator 15 makes minute positioning adjustments to platform 2 in order to accurately position dispense head 6 over slide 40 A2 at its first dispense position.
  • Dispense head 6 is then lowered via linear actuator 26 so that tips 7 are in contact with slide 40A2 at its first dispense position.
  • slide 40 A2 is completely spotted utilizing solution removed from removal positions 85 - 88.
  • Camera 12 and strobe 13 scans slide 40A2 and acquires images and inspects for spot quality. It is at this point that the control system identifies slide 40A2 as pass or fail.
  • dispense tips 7 are dipped in sonic cleaner 9. Dispense tips 7 are then rinsed in rinse fountain 10. Then, dispense tips 7 are dried in vacuum manifold 1 1. Preferably, dispense tips 7 are cleaned after every two slides have been completely spotted. However, the frequency of cleaning may be adjusted as is appropriate.
  • Linear actuator 26 is moved via linear actuator 21 to a position above microplate 601. Then, positioning adjustments are made to linear actuator 26 and to walking beam indexer 37 so that dispense head 6 is directly above microplate 601 at ninth removal position 89, as shown in FIG. 77. Solution is then removed from ninth removal position 85. As shown in FIG. 75, linear actuator 26 is then moved so that it is above slide 40A3. Based on the earlier positioning data regarding slide 40 A3, linear actuator 21 makes minute positioning adjustments to linear actuator 26 and linear actuator 15 makes minute positioning adjustments to platform 2 in order to accurately position dispense head 6 over slide 40A3 at its first dispense position.
  • Dispense head 6 is then lowered via linear actuator 26 so that tips 7 are in contact with slide 40A3 at its first dispense position.
  • slide 40A3 is completely spotted utilizing solution removed from removal positions 89 - 92.
  • walking beam indexer 37 moves slightly to the right, as shown in FIG. 76.
  • Linear actuator 26 is moved via linear actuator 21 to a position above microplate 601. Then, positioning adjustments are made to linear actuator 26 and to walking beam indexer 37 so that dispense head 6 is directly above microplate 601 at thirteenth removal position 93, as shown in FIG. 77. Solution is then removed from thirteenth removal position 93.
  • linear actuator 26 is then moved so that it is above slide 40A4. Based on the earlier positioning data regarding slide 40A4, linear actuator 21 makes minute positioning adjustments to linear actuator 26 and linear actuator 15 makes minute positioning adjustments to platform 2 in order to accurately position dispense head 6 over slide 40A4 at its first dispense position.
  • Dispense head 6 is then lowered via linear actuator 26 so that tips 7 are in contact with slide 40A4 at its first dispense position.
  • slide 40A2 is completely spotted utilizing solution removed from removal positions 93 - 96.
  • microplate lid 27 is moved via lid lifter 44 over microplate 601 at position ⁇ , as shown in FIG. 79. Microplate lid 27 is then lowered onto microplate 601, as shown in FIG. 54. Repeat Spotting Sequence for the Remaining Microplates 602 - 620 In FIG. 57, lid lifter 44 is raised, leaving behind microplate lid 27 on microplate 601. Input chamber singulator 23 and input chamber lifter 802 have has lowered input stack 603 - 620. Microplate 601 is at position ⁇ (FIG. 44B), microplate 602 is at position ⁇ , and microplate 603 is at position ⁇ . Walking beam indexer 37 has been lowered so that dowel pins 14 are below the horizontal plane formed by the top surface of beam 8.
  • walking beam indexer 37 has moved to the right.
  • Input chamber singulator 23 has lifted input stack 604 - 620, leaving behind microplate 603 at position ⁇ .
  • walking beam indexer 37 is raised so that dowel pin 14 is located directly behind microplate 603.
  • microplate 601 is at position ⁇
  • microplate 602 is at position ⁇
  • microplate 603 is at position ⁇ (FIG. 44B).
  • microplate lid 27 has been removed from microplate 602.
  • Solution has been removed from the first removal position of microplate 602 and is being deposited at the first dispense position of slide 40A5.
  • solution will continue to be removed from microplate 602 until slides 40A5 - 40A8 are completely spotted.
  • microplate 601 is at position ⁇ inside output chamber 502, microplate 602 is at position ⁇ , microplate 603 is at position ⁇ , and microplate 604 is at position ⁇ (FIG. 44B).
  • Dispense head 6 is positioned over slide 40A9. In a fashion similar to that describe above, solution will be removed from microplate 603 to spot slides 40A9 - 40B2.
  • microplate 602 is at position ⁇ inside output chamber 502 and underneath microplate 601, microplate 603 is at position ⁇ , microplate 604 is at position ⁇ , and microplate 605 is at position ⁇ (FIG. 44B).
  • Output chamber lifter 63 is shown in FIG. 42 and it used for restacking the microplates inside output chamber 502.
  • microplate 609 is at position ⁇ inside output chamber 502 and directly underneath microplate 608, microplate 610 is at position ⁇ , microplate 611 is at position ⁇ , and microplate 612 is at position ⁇ (FIG. 44B).
  • platform 2 has moved to the left via linear actuator 15. Locating plates 40E - 40H containing forty slides 40E1 - 40H10 have been placed on platform 2.
  • Microplate 609 is still at position ⁇ inside output chamber 502 and directly underneath microplate 608, microplate 610 is at position ⁇ , microplate 611 is at position ⁇ , and microplate 612 is at position ⁇ (FIG. 44B).
  • Lid lifter 44 has removed microplate lid 27 from microplate 61 1 and has retracted microplate lid 27 so that it is not above microplate lid 611.
  • FIG. 86 solution has been removed from microplates 611 - 620 and spotted on slides 40E1 - 40H10.
  • Microplates 601 - 620 are restacked inside output chamber 502 with microplate 601 at the top of the stack and microplate 620 at the bottom of the stack. Locating plates 40E - 40H have moved to the right and are ready to be removed.
  • Output Chamber Utilizing Output Chamber Lifter with Stack Support Pieces As shown in FIGS. 42, output chamber 502 has two stack support pieces 120 mounted to its side. Output chamber lifter 63 is directly under output chamber 502. FIG. 90 shows a perspective view of output chamber 502 with stack support pieces 120 mounted to its side. As shown in FIG. 42, output chamber lifter 63 has a single large lifting pad 63A. Single large lifting pad 63A provides a more stable support for the output stack than does the two lifting pad output chamber lifter depicted in U.S. Patent Application No. 09/611,256.
  • FIG. 90 shows a detailed perspective view of stack support piece 120 mounted to output chamber 502 and FIG. 91 shows a detailed side view of stack support piece 120 mounted to output chamber 502.
  • Mount 130 is rigidly attached to output chamber 502.
  • Axis 131 extends through mount 130 and stack support piece 120.
  • Torsion spring 132 is wound around axis 131 and applies a force to mount 130 and stack support piece 120. This force tends to rotate stack support piece 120 in a counter-clockwise direction (FIG. 91) so that tapered support end 134 extends through hole 133 until stack support piece 120 is abutted by output chamber 502.
  • FIGS. 92 - 95 A sequence illustrating the operation of output chamber 502 with stack support pieces 120 is seen by reference to FIGS. 92 - 95.
  • output stack 601 - 606 is in output chamber 502.
  • Microplate 606 is at the bottom of the output stack at position ⁇ (FIG. 44B).
  • Microplate 605 is above microplate 606 and is resting on stack support pieces 120
  • output chamber lifter 63 is lifting output stack 601 - 606 by pressing upward on microplate 606.
  • Tapered support end 134 of stack support piece 120 allows the upward movement of microplate 606.
  • output chamber lifter 63 has lifted microplate 606 beyond tapered support ends 134.
  • the force applied by torsion spring 132 against stack support piece 120 then moves tapered support end back through holes 133.
  • output chamber lifter 63 has lowered. Output stack 601 - 606 is resting on stack support pieces 120. The space at position ⁇ (FIG. 4) is clear to make room for the next microplate in the stack.
  • microplates are continually stacked in the output chamber of this preferred embodiment.
  • the embodiment utilizing output chamber lifter 63 in conjunction with stack support pieces 120 is a preferred method of stacking because a microplate can be moved into the output chamber without sliding against or contacting the microplate that is directly above it.
  • FIGS. 92 - 95 there is essentially no tipping of microplates in this embodiment. As the microplates are stacked, the base of upper microplate fits snuggly into the lid of the microplate immediately below it. This helps prevent microplates from becoming askew within the output chamber and helps prevent spillage of any solution contained within the microplates.
  • an advantage of the third preferred embodiment is that it enables a large number of slides to be automatically spotted from a large number of microplates.
  • a further advantage of the third preferred embodiment is found by the utilization of microplate indexing station 700.
  • the stacking and restacking capability of microplate indexing station 700 allows a large number of microplates to be indexed through position ⁇ without wasting significant horizontal space.
  • camera 12 and strobe 13 scans the slide and acquires images and inspects for spot quality. It is at this point that the control system identifies the slide as pass or fail. An operator monitoring the spotting process via a monitor has the option of correcting a slide that has failed.
  • an operator can scan a locating plate after the slides on it have been spotted.
  • a good plate shows up green as in all slides pass.
  • a plate with at least one bad spot on one of the slides shows up red.
  • the user can then zoom in on the bad slide and the good and bad spots show up green and red respectively as pass or fail. From there, the user can decide whether or not to rework the bad spots.
  • the procedure for reworking a failed spot was described above in reference to FIGS. 39 A and 39B.
  • the computer makes a determination whether or not a spot has passed or failed using the computer controlled pass-fail determination technique earlier described. If, based on its analysis, the computer determines that the spot has failed, the computer will automatically take steps to rework the spot. The procedure for automatically reworking a failed spot was also described above.
  • FIG. 40 A preferred embodiment is shown in which five dispense tips 42A - E extend down below dispense head 40.
  • dispense tips 42A - E are retractably connected to dispense head 40.
  • dispense tips 42A - D are retracted inside dispense head 40.
  • the rightmost dispense tip 42E is extended below the other dispense tips and is spotting slide 4A1.
  • dispense tips 42A - E are mounted to a pneumatic slides 43.
  • each dispense tip 42 can be configured to dispense a different volume of solution.
  • dispense tip 42A would dispense 1 nL of solution
  • dispense tip 42B would dispense 2 nL of solution
  • dispense tip 42C would dispense 4 nL of solution
  • dispense tip 42D would dispense 8 nL of solution
  • dispense tip 42E would dispense 16 nL of solution.
  • camera 12 and strobe 13 would work in conjunction to provide sensory data to PC control system 300 reporting the quality of the spots.
  • the spots would then be classified as pass or fail. If a spot has failed, the software in conjunction with PC control system 300 would determine the amount of solution required to correct the failed spot. Then, during the reworking sequence, the dispense tip that dispenses the most correct volume would be extended down from dispense head 40 and the other dispense tips would be retracted upward inside dispense head 40, as shown in FIG. 40.
  • the previous embodiments disclosed using a strobe light to illuminate the slide below the camera could be illuminated with other light sources besides a strobe light.
  • the slide could be illuminated with a camera flash, a constant bright light, or a fluorescence device, such as a fluorescent LED. If a fluorescence device is used to illuminate the slide, those of ordinary skill in the art will recognize that it is possible to add a fluorescent dye to the solution being spotted to achieve more in depth characterizations. For example, by using a fluorescent LED and adding fluorescent dye to the solution, greater volume determination can be achieved based on fluorescent intensity of the spot. Also, although vibration isolated base 80 was shown in FIG.
  • FIG. 37 showed touch screen monitor interface 305, other interfaces could also be utilized such as a keyboard interface.
  • PC control system 300 could be a laptop computer. This embodiment would achieve significant space savings.
  • dispense tips 7 and 42 were quill type dispense tips, it would be obvious to substitute other types of dispense tips. For example, piezo type dispense tips could also be used.
  • each slide has its own unique 2D bar code 65 for identification purposes.
  • an infrared camera capable of emitting and receiving infrared signals, is mounted to the side of linear actuator 26.
  • each slide is made of a material that that is transparent to infrared energy, such as silicon.
  • Each slide is then marked for identification purposes on its back with a marking that is reflective of infrared energy, such as a foil marking or paint marking.
  • the infrared camera then identifies the slide by its infrared reflective marking after emitting the slide with infrared energy. Accordingly the reader is requested to determine the scope of the invention by the appended claims and their legal equivalents, and not by the examples which have been given.

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Abstract

L'invention concerne une unité de formation de microréseaux à haut capacité servant à effectuer des dépôts de solution sur des microplaquettes dans un dispositif de distribution de microréseaux automatisé. Un dispositif d'indexation de microplaques déplace automatiquement, en séquence, plusieurs microplaques vers une zone d'évacuation de solution. Une tête de distribution, qui accède à chaque microplaque dans la zone d'évacuation de solution, enlève la solution de la microplaque. Ladite tête se déplace ensuite vers une station de positionnement de microplaquettes pour déposer des traces sur les microplaquettes au niveau de la station de positionnement de microplaquettes. Dans un mode de réalisation préféré, la station d'indexation de microplaques est pourvue d'au moins une chambre d'empilement d'entrée conçue pour empiler des microplaques, et d'au moins une chambre d'empilement de sortie pour empiler des microplaques. Un indexeur de balancier est disposé entre les chambres d'empilement d'entrée et de sortie. L'indexeur de balancier permet de déplacer des microplaques de la chambre d'empilement d'entrée vers la chambre d'empilement de sortie. Au niveau de la zone d'évacuation de solution, une souleveuse de couvercle soulève le couvercle de chaque microplaque afin de permettre à la tête de distribution d'accéder à la microplaque en vue de l'évacuation de solution. Une fois la solution évacuée, la souleveuse de couvercle remet le couvercle en place. Dans un autre mode de réalisation, au moins une source lumineuse éclaire les microplaquettes, et au moins une caméra fonctionne en corrélation avec la source lumineuse. La caméra est capable d'acquérir des données image de microplaquettes et de les transmettre à un ordinateur. Ce dernier, qui est programmé pour recevoir et analyser lesdites données image, génère ensuite des données de post-analyse fondées sur l'analyse des données image de microplaquettes. Les données de post-analyse sont destinées à améliorer le dépôt de solution sur les microplaquettes. Dans un mode de réalisation préféré, les données image de microplaquettes renferment des informations se rapportant à l'alignement des microplaquettes, à la qualité de la trace et à l'identification des microplaquettes. Dans un mode de réalisation préféré, l'analyse des informations relatives à l'alignement des microplaquettes permet à l'ordinateur d'effectuer des réglages automatiques par rapport aux positions relatives de la tête de distribution et des microplaquettes afin d'augmenter la précision du dépôt. Dans un mode de réalisation, l'analyse des informations relatives à la qualité du dépôt identifie ce dernier comme accepté ou rejeté. Un opérateur peut alors retravailler le dépôt. Dans le mode de réalisation préféré, l'analyse des informations d'identification des microplaquettes permet à l'ordinateur de suivre chaque microplaquette.
PCT/US2001/045446 2000-10-30 2001-10-30 Distribution de microreseaux a haute capacite WO2002064812A2 (fr)

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EP01270118A EP1337337A2 (fr) 2000-10-30 2001-10-30 Distribution de microreseaux a haute capacite
AU2002253796A AU2002253796A1 (en) 2000-10-30 2001-10-30 High capacity microarray dispensing

Applications Claiming Priority (2)

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US69681800A 2000-10-30 2000-10-30
US09/669,818 2000-10-30

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WO2002064812A3 WO2002064812A3 (fr) 2003-02-27

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US7875245B2 (en) 2003-05-14 2011-01-25 Dako Denmark A/S Method and apparatus for automated pre-treatment and processing of biological samples
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Publication number Priority date Publication date Assignee Title
EP1548437A1 (fr) * 2002-09-17 2005-06-29 Olympus Corporation Procede et appareil d'agencement de constituants par reaction de liquide sur une surface de substrat pour la detection d'une substance cible par la reaction de constituants multiples sur substrate et elements utilises dans le procede
EP1548437A4 (fr) * 2002-09-17 2006-06-07 Olympus Corp Procede et appareil d'agencement de constituants par reaction de liquide sur une surface de substrat pour la detection d'une substance cible par la reaction de constituants multiples sur substrate et elements utilises dans le procede
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US7678568B2 (en) 2002-11-19 2010-03-16 Sanyo Electric Co., Ltd. Incubator
US8257968B2 (en) * 2002-12-20 2012-09-04 Dako Denmark A/S Method and apparatus for automatic staining of tissue samples
US9599630B2 (en) 2002-12-20 2017-03-21 Dako Denmark A/S Method and apparatus for automatic staining of tissue samples
US7025935B2 (en) 2003-04-11 2006-04-11 Illumina, Inc. Apparatus and methods for reformatting liquid samples
US7875245B2 (en) 2003-05-14 2011-01-25 Dako Denmark A/S Method and apparatus for automated pre-treatment and processing of biological samples
EP2022736A1 (fr) * 2006-05-16 2009-02-11 Rorze Corporation Dispositif de transport de type navette, dispositif d'alimentation et de collecte de microplaque, dispositif de retrait de microplaque, cassette de microplaque et tablette destinée à recevoir une microplaque
EP2022736A4 (fr) * 2006-05-16 2012-09-19 Rorze Corp Dispositif de transport de type navette, dispositif d'alimentation et de collecte de microplaque, dispositif de retrait de microplaque, cassette de microplaque et tablette destinée à recevoir une microplaque

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EP1337337A2 (fr) 2003-08-27
AU2002253796A1 (en) 2002-08-28
AU2002253796A8 (en) 2002-08-28
WO2002064812A3 (fr) 2003-02-27

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