Automated sample analysis system and method

• US 20040256963A1
• Filed: 01/30/2004
• Published: 12/23/2004
• Est. Priority Date: 01/31/2003
• Status: Active Grant

• Current Assignee: NEXUS Biosystems, Inc. (Azenta, Inc.)
• Original Assignee: Discovery Partners International, Inc. (Infinity Pharmaceuticals, Inc.)
• Inventors: Neeper, Robert K., Affleck, Rhett L., Lillig, John E., Levin, Robert K., Bodnar, Mike
• Granted Patent: US 7,596,251 B2
• Time in Patent Office: Days
• US Class Current: 312/209
• CPC Class Codes: B01L 9/523 for multisample carriers, e.g. used for microtitration plates
• CPC Class Codes: C30B 29/58 Macromolecular compounds
• CPC Class Codes: C30B 7/00 Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions from molten solvents C30B9/00; by normal or gradient freezing C30B11/00; under a protective fluid C30B27/00
• CPC Class Codes: G01N 15/1433 using image recognition
• CPC Class Codes: G01N 2001/4027 evaporation leaving a concentrated sample
• CPC Class Codes: G01N 2015/1493 Particle size
• CPC Class Codes: G01N 2035/00356 Holding samples at elevated temperature (incubation)
• CPC Class Codes: G01N 2035/00455 Controlling humidity in analyser
• CPC Class Codes: G01N 2035/00881 network configurations
• CPC Class Codes: G01N 2035/042 moved independently, e.g. by fork manipulator
• CPC Class Codes: G01N 2035/0425 Stacks, magazines or elevators for plates
• CPC Class Codes: G01N 2035/0463 in incubators
• CPC Class Codes: G01N 21/253 for batch operation, i.e. multisample apparatus analytical automats G01N35/00
• 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: G02B 21/0016 Technical microscopes, e.g. for inspection or measuring in industrial production processes

Abstract

An automated biological sample analysis system and method for use in incubating and analyzing multiple samples for protein crystallization. A temperature controlled cabinet houses sample storage, sample transport, and sample imaging systems. The operation of the system is automated and can be controlled by software, which can be reconfigured remotely. An array of storage shelves includes multiple shelf columns arranged around a core. Multiple banks of removable shelves arranged as magazines are accessed through a door on the cabinet. Each shelf stores a multi-well plate and different sizes can be stored in different shelves. The core houses a sample transport system that includes a multi-axis robot that rotates about a vertical axis to access the shelves in the shelf array. The transport system retrieves and replaces the multi-well plates in the shelves and can move plates from the shelves to an imaging system where each sample can be automatically imaged.

Claims

1. An automated multi-well plate imaging system comprising:

a cabinet configured to selectively provide a stabilized temperature within an interior of the cabinet;

a plurality of shelves within the interior of the cabinet, each shelf configured to store a multi-well plate;

a transport assembly, within the cabinet, configured to retrieve the multi-well plate from one of the plurality of shelves and transport the multi-well plate to a destination; and

an optical assembly configured to receive the multi-well plate from the transport assembly as the destination and image at least a portion of the multi-well plate.

2. The system of claim 1, further comprising a filter plate that is moved by the transport assembly to a location between the multi-well plate and an imaging device at the optical assembly.

3. The system of claim 2, wherein the filter plate comprises a polarization filter.

4. The system of claim 1, further comprising a plate adapter that is moveable by the transport assembly to a location at the optical assembly;

the plate adapter being configured to hold a small multi-well plate having smaller dimensions than the multi-well plate.

5. The system of claim 1, further comprising a plate tray configured to house one or more multi-well plates.

6. The system of claim 1, further comprising:

a door attached to a front of the cabinet and configured to provide access to the interior of the cabinet; and

a plate access door attached to the front of the cabinet and configured to provide access to a selected multi-well plate.

7. The system of claim 6 wherein the transport assembly retrieves the selected multi-well plate from one of the plurality of shelves and transports the selected multi-well plate to the plate access door.

8. The system of claim 1, further comprising a plurality of removable shelves configured to be selectively attached to the interior of the cabinet and configured to store a multi-well plate, and wherein the transport assembly is further configured to retrieve the multi-well plate from the plurality of removable shelves.

9. The system of claim 1, further comprising:

a thermal regulation unit configured to maintain the stabilized temperature within an interior of the cabinet; and

an isolation assembly connected to the thermal regulation unit and the cabinet and configured to substantially mechanically isolate the thermal regulation unit from the cabinet during an operating period and mechanically locate the thermal regulation unit to the cabinet during a cabinet transport period.

10. An automated multi-well plate imaging system comprising:

a plurality of stationary shelves arranged in an arc, each of the plurality of stationary shelves configured to store a multi-well plate;

a transport assembly having a rotatable platform mounted within the inside of the arc, the elevator assembly configured to retrieve a first multi-well plate from the plurality of stationary shelves and transport the first multi-well plate to a destination.

11. The system of claim 10, further comprising an optical assembly configured to receive the first multi-well plate from the transport assembly and image at least a portion of the first multi-well plate.

12. The system of claim 10, wherein the plurality of stationary shelves are arranged in substantially a circular arc and wherein the rotatable platform includes an axis of rotation located at substantially a center of the circular arc.

13. A method of imaging at least a portion of a multi-well plate, the method comprising:

storing the multi-well plate on a shelf at a selected environment;

retrieving the multi-well plate from the shelf using an automated multi-well plate transport assembly;

transporting, at the selected environment, the multi-well plate to an optical assembly using the automated multi-well plate transport assembly;

autonomously imaging, at the selected environment, at least a portion of the multi-well plate using the optical assembly; and

transporting the multi-well plate from the optical assembly to the shelf using the automated multi-well plate transport assembly; and

repositioning the multi-well plate in the shelf.

14. A multi-well plate transport assembly for use in a crystallization imaging system, the assembly comprising:

a rotatable platform;

an elevator assembly mounted on the rotatable platform; and

a plate handler connected to the elevator assembly and configured to retrieve a multi-well plate from a first location and deliver the multi-well plate to a second location.

15. The multi-well plate transport assembly of claim 14, further comprising another plate handler connected to the elevator assembly and configured to retrieve a multi-well plate, wherein the elevator assembly is configured to move the first and second plate handlers at least up and down in order to retrieve multi-well plates.

16. A method of transporting a multi-well plate in an automated crystallization imaging system, the method comprising:

rotating a plate handler to a first predetermined angular position;

transporting the plate handler to a first vertical position;

retrieving the multi-well plate from a shelf using the plate handler;

transporting the plate handler to a second vertical position;

rotating the plate handler to a second angular position; and

delivering the multi-well plate to a destination.

17. A method of transporting a multi-well plate in an automated crystallization imaging system, the method comprising:

positioning a plate handler at a first shelf;

retrieving a first multi-well plate having a first size from the first shelf using the plate handler;

transporting the first multi-well plate to a destination;

delivering the first multi-well plate to the destination;

positioning the plate handler at a second shelf; and

retrieving a second multi-well plate having a second size from the second shelf.

18. A method of transporting a multi-well plate in an automated crystallization imaging system, the method comprising:

raising a first edge of the multi-well plate above a surface of a shelf while maintaining contact between a second edge of the multi-well plate and the surface of the shelf;

transporting the multi-well plate onto a surface of a plate handler while maintaining contact between the second edge and the surface of the shelf; and

raising the second edge of the shelf above the surface of the shelf using a fulcrum.

19. An optical assembly for use in an automated crystallization imaging system, the optical assembly comprising:

an automated movable mount configured to be selectively positioned along a first axis;

a lens having motorized focus attached to the movable mount;

an imaging device attached to the lens and configured to automatically capture an image within the lens focal length.

20. The optical assembly of claim 19, further comprising an automated multi-well plate positioning device configured to selectively position a multi-well plate along a second axis substantially perpendicular to the first axis.

21. An optical assembly for use in an automated crystallization imaging system, the optical assembly comprising:

a mount configured to support a multi-well plate;

a lens attached to a movable mount, wherein the movable mount is configured to selectively move the lens in a first direction and in a second direction perpendicular to the first direction;

an imaging device coupled to the lens and configured to automatically capture an image of at least a portion of the multi-well plate using the lens, wherein selective movement of the lens in the first direction and the second direction allows movement of the lens so that the imaging device may captures images of substantially any portion of the multi-well plate.

22. A method of automated imaging at least a portion of a multi-well plate, the method comprising:

positioning the multi-well plate along a first axis;

positioning an imaging device along a second axis substantially perpendicular to the first axis; and

capturing an image of at least a portion of the multi-well plate.

23. An optical assembly for use in an automated crystallization imaging system, the optical assembly comprising:

an imaging device configured to capture an image of at least a portion of a multi-well plate; and

a lighting device configured to illuminate the at least a portion of the multi-well plate with an adjustable light intensity.

24. The optical assembly of claim 23, wherein the at least a portion of a multi-well plate includes a portion of a well.

25. A device for use in an automated crystallization imaging system, the device comprising:

an imaging device;

an area of interest on a multi-well plate;

an optical axis extending from a lens of the imaging device to the area of interest on the multi-well plate;

a first light source positioned away from the imaging axis by a first distance so that light emitted from the first light source that is incident on the area of interest on the multi-well plate is off-axis from the imaging axis.

26. The device of claim 25, wherein the area of interest on the multi-well plate includes at least a portion of a well.

27. The device of claim 25, further comprising:

a second light source positioned away from the imaging axis by a second distance, the second light source positioned substantially opposite the imaging axis from the first light source.

28. A method of adjusting a light intensity in an automated crystallization imaging system, the method comprising:

charging a first capacitor;

connecting the first capacitor to a flash tube to generate flash illumination; and

controlling a period of time the first capacitor is connected to the flash tube to adjust the illumination from the flash tube.

29. The method of claim 28, wherein connecting the first capacitor to the flash tube comprises activating an SCR connecting the first capacitor to the flash tube.

30. The method of claim 29, wherein controlling the period of time the first capacitor is connected to the flash tube comprises momentarily interrupting a current flow through the SCR using a second capacitor.

31. A shelf for use in an automated crystallization imaging system, the shelf comprising:

a support surface having a recess to provide access to at least a portion of a bottom of a multi-well plate positioned on the shelf;

a first rail on the support surface configured to position, on the support surface, a first multi-well plate having a first outline.

32. The shelf of claim 31, wherein the first rail comprises outer walls on opposites sides of the support surface.

33. The shelf of claim 31, further comprising a second rail on the support surface configured to position, on the support surface, a second multi-well plate having a second outline.

34. The shelf of claim 31, further comprising first and second side surfaces having mounting guides configured to align a first shelf with a second shelf along a vertical axis.

35. The shelf of claim 31, further comprising:

a side surface; and

a tab extending from the side surface and configured to cooperate with a sensor to provide information relating to a position relative to the support surface.

36. A refrigerated sample storage cabinet, comprising:

a plurality of sample shelves inside the cabinet; and

a compressor assembly associated with the cabinet, wherein the compressor assembly is movable from a first position to a second position, wherein, in the first position, the compressor assembly is mounted to the cabinet, and in the second position, the compressor assembly is not mounted to the cabinet but instead the compressor assembly and the cabinet are both adapted to sit separately on a floor or other support surface, thereby providing vibration isolation between the cabinet and the compressor assembly.

37. A robotic sample analysis system, comprising:

a sample analysis station;

a sample storage area containing a plurality of sample holders;

a robotic sample moving assembly adapted to transport sample holders between the analysis station and the storage area, the sample moving assembly including a first receptacle and a second receptacle, each receptacle adapted to receive and transport a sample holder; and

software controlling the operation of the sample moving assembly such that while a first sample holder is in the analysis station, the sample moving assembly retrieves a second sample holder into the second receptacle, and then moves the first sample holder from the analysis station into the first receptacle and moves the second sample holder into the analysis station prior to returning the first sample holder into the storage area and retrieving a third sample holder.

38. A self-contained sample storage and analysis station, comprising:

a temperature-controlled cabinet;

a plurality of fixed sample storage receptacles arranged at least partially around a central core area in the cabinet;

at least one accessible sample receptacle located on at least one side of the central core area, wherein the accessible sample receptacle is accessible from outside of the cabinet, such that a sample outside of the cabinet can be inserted into the cabinet via the accessible sample receptacle;

a robotic sample mover located in the central core area, the robotic sample mover being rotatable about a vertical axis and movable up and down that axis to move samples between the accessible sample receptacle and the fixed sample storage receptacles.

39. The sample storage and analysis station of claim 38, further comprising a sample analysis station in the cabinet adjacent to the central core area, wherein the robotic sample mover is adapted to move samples between the fixed sample storage receptacles and the sample analysis station.

40. A method for performing protein crystallography, comprising:

storing a plurality of crystallography sample plates in sample storage receptacles in a temperature-controlled cabinet, said cabinet also having a robotic sample handler and an imaging station therein;

retrieving a sample plate with the robotic sample handler by sliding the sample plate horizontally from its sample storage receptacle onto a sample plate holder;

robotically moving the sample plate and sample plate holder to the imaging station; and

horizontally sliding the sample plate into the imaging station.

41. The method of claim 40, wherein the sample plate is slid at a speed of no more than 1 cm/second.

42. The method of claim 40, wherein the robotic sample mover is mounted for rotation about a vertical axis, and wherein the step of robotically moving the sample plate to the imaging station is accomplished by vertical and rotational movement of the robotic sample mover on said axis.

43. The method of claim 40, wherein sliding of the sample plate is accomplished by robotically raising a first end of the plate and horizontally moving the plate so that it slides on a second end of the plate.