Automated system for simultaneously performing a plurality of signal-based assays

• US 6,746,864 B1
• Filed: 06/05/1995
• Issued: 06/08/2004
• Est. Priority Date: 08/08/1994
• Status: Expired due to Term

• Current Assignee: Leidos, Inc. (Leidos Holdings, Inc.)
• Original Assignee: Merck & Co., Inc., Science Applications International Corporation
• Inventors: Velicelebi, Gonul, Karlton, David Philip, Akong, Michael Anthony, Mierzeski, Donald James, McNeil, John Austin
• Primary Examiner(s): GITOMER, RALPH J
• Application Number:
  US08/465,354
• Time in Patent Office: 3,291 Days
• Field of Search: 435/29, 435/4, 435/288.7, 356/414, 356/418, 356/419, 356/435, 356/440, 250/328
• US Class Current: 435/288.7
• CPC Class Codes: B01J 2219/00315 Microtiter plates
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/00659 Two-dimensional arrays
• CPC Class Codes: B01J 2219/00689 using computers
• CPC Class Codes: B01J 2219/00695 Synthesis control routines, e.g. using computer programs
• CPC Class Codes: B01J 2219/00702 Processes involving means for analysing and characterising the products
• CPC Class Codes: C40B 60/14 for creating libraries
• CPC Class Codes: G01N 2035/00752 bar codes
• CPC Class Codes: G01N 2035/0093 random access not determined by physical position
• CPC Class Codes: G01N 33/5302 Apparatus specially adapted for immunological test procedures
• CPC Class Codes: G01N 33/5304 Reaction vessels, e.g. agglutination plates for solid-phase systems G01N33/543
• CPC Class Codes: G01N 35/0092 Scheduling
• CPC Class Codes: G01N 35/0099 comprising robots or similar manipulators robots per se B25J
• CPC Class Codes: G01N 35/028 having reaction cells in the form of microtitration plates
• CPC Class Codes: G01N 35/1065 Multiple transfer devices
• CPC Class Codes: Y10T 436/115831 Condition or time responsive

Abstract

An automated detection system includes a robotic fluid handling system for performing assays on the plurality of test samples; a detection system for imaging the assays as they are performed; and a computer control, data acquisition, and data analysis system for controlling the operation of the detection system and for collecting and analyzing imaging data. The automated detection system comprises a pipettor for simultaneously distributing a predetermined amount of a reagent to each of the plurality of samples containing a fluorescent dye or other indicator moiety; an excitation source for simultaneously exciting a fluorescent reaction of the fluorescent dye indicating the intensity of reaction between a sample and the reagent in each of the sample wells; a detector for detecting signal produced by the reaction in each of the sample wells over a period of time comprising a single CCD scanning device for optically scanning the plurality of samples simultaneously; and computerized controller for simultaneously coordinating the pipettor, the excitation source, and the detector.

Claims

1. An apparatus for simultaneously performing a plurality of fluorescence assays using a plate containing a plurality of wells, said apparatus comprising:

an excitation system configured to project excitation radiation uniformly onto a surface of said plate so as to simultaneously illuminate said plurality of wells, the excitation system including;

a radiation source configured to generate the excitation radiation, and

an elliptical mirror configured to receive the excitation radiation from the radiation source and to reflect the excitation radiation,

thereby producing a uniform source of excitation radiation for projection onto the plate and the plurality of wells and a detection system configured to detect an image of fluorescence emitted from each of the plurality of wells simultaneously.

2. The apparatus according to claim 1, wherein said excitation system provides excitation radiation at a plurality of wavelengths.

3. The apparatus according to claim 1, further comprising filter means positioned in a light path of said excitation system, wherein said filtering means provides excitation radiation of a plurality of wavelengths.

4. The apparatus according to claim 1, further comprising a plate handling means for automatically lifting, carrying and positioning a plurality of plates to enable automated testing of said plurality of plates.

5. An apparatus for simultaneously performing a plurality of fluorescence assays using a plate including a plurality of wells distributed throughout at least a portion of the plate, the apparatus comprising:

an excitation system configured to project excitation radiation uniformly onto the portion of the plate throughout which the plurality of wells are distributed, thereby simultaneously and uniformly illuminating both the plurality of wells and the portion that is disposed between each of the plurality of wells; and

a detection system configured to detect an image of fluorescence emitted from each of the plurality of wells simultaneously and continuously over a predetermined period of time.

6. The apparatus of claim 5, further including a collimating lens through which the excitation radiation passes prior to reaching the portion of the plate.

7. The apparatus of claim 5, wherein the excitation system includes an output from which the excitation radiation is projected, the detection system includes an input for receiving said image of fluorescence, and the output of the excitation system and the input of the detection system are both on a same side of the plate and are both optically aligned with the plate along a same imaginary axis.

8. The apparatus of claim 7 wherein the excitation system includes a fold mirror disposed between said input of the dection system and the plate.

9. The apparatus of claim 5, wherein the image comprises an entire view of each of said plurality of wells.

10. An apparatus for scheduling and performing a plurality of fluorescence assays using a plurality of plates each including a plurality of wells, the apparatus comprising:

an excitation system configured to project, for each plate, excitation radiation uniformly onto a portion of the respective plate throughout which the plurality of wells are distributed, thereby simultaneously and uniformly illuminating both the plurality of wells and the portion that is disposed between each of the plurality of wells;

a detection system configured to detect for each plate, an image of fluorescence emitted from each of the plurality of wells on the respective plate simultaneously;

a memory configured to store data representing at least first and second tracks and representing at least one critical point at which the first and second tracks are tied together in time, each of the first and second tracks defining a set of assay operations in time, at least a portion of the first track to be performed simultaneously with the second track;

a robotic device configured to perform at least a portion of the sets of assay operations on at least one of the plates; and

a scheduler configured to control the robotic device to finish a portion of the set of assay operations of the second track defined prior to the critical point before allowing the robotic device to begin a portion of the set of assay operations of the first track defined after the critical point,

thereby providing for a more fully optimized scheduling of the assay operations.

11. The apparatus of claim 10 wherein the scheduler is configured to determine a total time to run all of the sets of assay operations of the first and second tracks.

12. The apparatus of claim 11 wherein the scheduler is further configured to automatically rearrange at least a portion of the sets of assay operations of at least one of the first and second tracks according to the total time to run all of the sets of assay operations of the first and second tracks.

13. The apparatus of claim 10 including a graphic user interface for allowing a user to define the first and second tracks.

14. An apparatus for simultaneously performing a plurality of fluorescence assays using a plate containing a plurality of wells, the apparatus comprising:

a detector configured to detect fluorescence emitted from each of the plurality of wells simultaneous and for generating data representing the fluorescence an excitation system configured to project excitation radiation uniformly onto a portion of the plate throughout which the plurality of wells are distributed, thereby simultaneously and uniformly illuminating both the plurality of wells and the portion that is disposed between each of the plurality of wells;

a processor connected to the detector and configured to receive the data representing the fluorescence and generate a real or pseudo-real time graphical representation of a status of the fluorescence emitted from each of the plurality of wells; and

a display connected to the processor and configured to display in real or pseudo real time the graphical representation of the status of the fluorescence emitted from each of the plurality of wells, the graphical representation indicating an arrangement in the plate of the plurality of wells,

wherein the real or pseudo-real time graphical representation includes a plurality of regions each having a particular color or a particular pseudo-color depending upon the status of at least one of the plurality of wells,

thereby allowing a user to view the plurality of wells all at once and to more easily correlate the graphical representation with each of the plurality of wells of the plate.

15. The apparatus of claim 14 wherein the real or pseudo-real time graphical representation includes a plurality of regions each having a particular amount of brightness depending upon the status of at least one of the plurality of wells.

16. An apparatus for simultaneously performing a plurality of fluorescence assays using a plate including a plurality of wells distributed throughout at least a portion of the plate, the apparatus comprising:

an excitation device configured to alternately project uniformly both a first excitation radiation having a first wavelength and a second excitation radiation having a second wavelength onto the portion of the plate throughout which the plurality of wells are distributed,

thereby simultaneously and uniformly illuminating both the plurality of wells and the portion that is disposed between each of the plurality of wells;

a detector configured to detect a first fluorescence emitted from each of the plurality of wells in response to the first excitation radiation and a second fluorescence emitted from each of the plurality of wells in response to the second excitation radiation and for generating data representing an amount of the first and second fluorescence for each of the plurality of wells simultaneously; and

a processor configured to receive the data and divide the amount of the first fluorescence of at least one of the wells by the amount of the second fluorescence of the at least one of the wells to generate a test result.

17. An apparatus for simultaneously performing a plurality of fluorescence assays using a plate including a plurality of wells distributed throughout at least a portion of the plate, the apparatus comprising:

an excitation system configured to project excitation radiation uniformly onto the portion of the plate throughout which the plurality of wells are distributed, thereby simultaneously and uniformly illuminating both the plurality of wells and the portion that is disposed between each of the plurality of wells; and

a detector configured to detect a simultaneous image of fluorescence emitted from the plurality of wells.

18. The apparatus of claim 17, wherein the detector comprises an imaging system for receiving at least a portion of fluorescence radiation generated from the plurality of wells, the imaging system generating data representing a time series of images of the at least the portion of fluorescence ration.

19. The apparatus of claim 17, wherein the image comprises an entire view of each of the plurality of wells.

20. The apparatus of claim 17, further including a mirror disposed so as to redirect the excitation radiation toward the plate, the mirror being disposed between the plate and the detector such that the at least a portion of fluorescence radiation passes through the mirror prior to being received by the detector.

21. The apparatus of claim 17, further including a collimating lens through which the excitation radiation passes prior to reaching the portion of the plate.

22. An apparatus for simultaneously performing a plurality of fluorescence assays using a plate including a plurality of wells, the apparatus comprising:

an excitation system configured to project excitation radiation uniformly onto a surface of the plate including the plurality of wells, thereby simultaneously and uniformly illuminating the plurality of wells;

a detection system configured to simultaneously detect at least a portion of fluorescence radiation generated from the plurality of wells; and

a mirror disposed so as to redirect the excitation radiation toward the surface of the plate, the mirror being disposed between the plate and the detection system such that the at least a portion of fluorescence radiation passes through the mirror prior to being received by the detection system.