Multiple fluid sample processor and system

• US 6,485,690 B1
• Filed: 05/27/1999
• Issued: 11/26/2002
• Est. Priority Date: 05/27/1999
• Status: Expired due to Fees

• Current Assignee: Orchid Biosciences Incorporated (Laboratory Corporation Of America Holdings)
• Original Assignee: Orchid Biosciences Incorporated (Laboratory Corporation Of America Holdings)
• Inventors: Swenson, Rolf E., Pfost, Dale R., DeWitt, Sheila H., Kugelmass, Sheldon M., Schnerr, Gary J., Lin, Chao, Juncosa, Robert D.
• Primary Examiner(s): Warden, Jill
• Assistant Examiner(s): Handy, Dwayne K
• Application Number:
  US09/321,410
• Time in Patent Office: 1,279 Days
• Field of Search: 422/63, 422/68.1, 422/99-104, 422/130, 422/131, 422/134, 436/174, 436/175, 436/179, 436/180
• US Class Current: 422/552
• CPC Class Codes: B01J 19/0046 Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays synthesis methods per se C40B50/00
• CPC Class Codes: B01J 2219/00286 Reactor vessels with top and bottom openings
• CPC Class Codes: B01J 2219/00315 Microtiter plates
• CPC Class Codes: B01J 2219/00317 Microwell devices, i.e. having large numbers of wells
• CPC Class Codes: B01J 2219/00319 the blocks being mounted in stacked arrangements
• CPC Class Codes: B01J 2219/00351 Means for dispensing and evacuation of reagents
• CPC Class Codes: B01J 2219/00364 Pipettes
• CPC Class Codes: B01J 2219/00389 Feeding through valves
• CPC Class Codes: B01J 2219/00416 Vacuum
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/00691 using robots
• 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: B01J 2219/00707 separated from the reactor apparatus
• CPC Class Codes: B01J 2219/0072 Organic compounds
• CPC Class Codes: B01J 2219/00722 Nucleotides
• CPC Class Codes: B01J 2219/00725 Peptides
• CPC Class Codes: B01J 2219/00745 Inorganic compounds
• CPC Class Codes: B01J 2219/00747 Catalysts
• CPC Class Codes: B01L 3/5025 for parallel transport of multiple samples
• CPC Class Codes: B01L 3/50255 : Multi-well filtration
• CPC Class Codes: C40B 30/08 : by measuring catalytic activity
• CPC Class Codes: C40B 40/06 : Libraries containing nucleotides or polynucleotides, or derivatives thereof
• CPC Class Codes: C40B 40/10 : Libraries containing peptides or polypeptides, or derivatives thereof
• CPC Class Codes: C40B 40/18 : Libraries containing only inorganic compounds or inorganic materials
• CPC Class Codes: C40B 60/14 : for creating libraries
• CPC Class Codes: Y10T 436/25 : including sample preparation
• CPC Class Codes: Y10T 436/25625 : Dilution
• CPC Class Codes: Y10T 436/2575 : Volumetric liquid transfer

Abstract

Multiple fluid sample processors and systems for high throughput chemical synthesis and biological assays and/or processing. A multi-layered fluidic array having microchannels, reservoirs and reaction wells is subject to robotic and automated handling. A pressure pumping system is utilized for fluid delivery and control through the synthesis process. The sizes of the micro-sized channels, apertures, and valves are adjusted to optimize fluid distribution and channel filling. The fluid sample processors can be grouped together in a microtiter format to increase the speed, quantity and efficiency of the processing.

Claims

1. A fluid sample processing apparatus comprising:

a reservoir plate member;

a distribution plate member connected to said reservoir plate member; and

a well plate member connected to said distribution plate member;

said reservoir plate member having an upper surface and a lower surface and a first plurality of orifices in the upper surface for entry of liquids therein, and a plurality of second orifices on the lower surface for exhausting of liquids from said reservoir plate member, said first and second plurality of orifices being spatially oriented;

a first plurality of micro-sized channels in said reservoir plate member for conveying liquids from said first plurality of orifices to said plurality of second orifices;

said distribution plate member having an upper surface and a lower surface and a plurality of third orifices in said upper surface of said distribution plate member, said third orifices being spatially arranged in alignment with said second plurality of orifices in said reservoir plate member in order to transfer liquids from said reservoir plate member to said distribution plate member;

a second plurality of micro-sized channels in said distribution plate member for fluid communication between the orifices on the upper surface of the distribution plate member and a plurality of fourth orifices on the lower surface of said distribution layer;

said well plate member having a plurality of well members therein, said well members having first openings in alignment with said plurality of fourth orifices of said distribution plate member; and

a pressurized fluid delivery mechanism, said mechanism positioned in contact with said reservoir plate member for selectively applying pressure into a plurality of first orifices in order to convey liquid materials through said apparatus.

2. The fluid sample processing apparatus as recited in claim 1 wherein said well plate member is releasably connected to said distribution plate member.

3. The fluid sample processing apparatus as recited in claim 1 wherein said well plate member is permanently bonded to said distribution plate member.

4. The fluid sample processing apparatus as recited in claim 1 wherein said well members have second openings therein for exhaustion of materials from said well members.

5. The apparatus as recited in claim 4 further comprising a collection plate layer positioned adjacent to said well plate member and having a plurality of collection members therein for collecting materials exhausted from said well members.

6. The apparatus as recited in claim 5 further comprising a spacing Member positioned between said well plate member and said collection plate member.

7. The apparatus as recited in claim 4 further comprising a heating plate member positioned adjacent to said well plate member for heating of materials placed in said well members.

8. The apparatus as recited in claim 1 wherein at least a portion of said second plurality of micro-sized channels in said distribution plate member are increased in size in order to control the distribution of a variety of materials with different fluidic properties.

9. The apparatus as recited in claim 1 wherein at least a portion of said second plurality of micro-sized channels increase sequentially in size along at least a portion of the surface of said distribution plate member.

10. An apparatus as set forth in claim 9 wherein said micro-sized channels increase sequentially in size toward the center of the distribution plate member.

11. The apparatus as recited in claim 1 wherein first micro-sized valve means are provided in communication with said plurality of third orifices in said distribution plate member.

12. The apparatus as recited in claim 1 wherein said sealing member is an elastomer member having a first plurality of openings positioned in alignment with said plurality of fourth orifices on said distribution plate member and a second plurality of opening positioned between said first plurality of openings, wherein said sealing member is altered in cross section, said elastomeric material can flow into said second openings.

13. The apparatus as recited in claim 1 wherein said sealing member is made from a material selected from the group comprising silicon, neoprene, and perfluro elastomer.

14. The apparatus as recited in claim 1 wherein said sealing member is a liquid coating material.

15. The apparatus as recited in claim 1 wherein said reservoir plate member is made from a material selected from the group comprising glass, fused silica, quartz, silicon, plastic, ceramic, tetrafluoroethylene, steel, stainless steel, aluminum and alloys of steel and aluminum.

16. The apparatus as recited in claim 1 wherein said distribution plate member is made from a material selected from the group comprising glass, fused silica, quartz, silicon, plastic, ceramic, tetrafluoroethylene, steel, stainless steel, aluminum and alloys of steel and aluminum.

17. The apparatus as recited in claim 1 wherein said well plate member is made from a material selected from the group comprising glass, tetrafluoroethylene, steel, stainless steel, aluminum and alloys of steel and aluminum.

18. The apparatus as recited in claim 1 wherein said distribution plate member and said well plate member are pretreated with materials selected from the group comprising silicon dioxide, silicon nitride, silicon carbide, titanium, tetrafluoroethylene, and silane.

19. The apparatus as recited in claim 1 wherein said first and second plurality of micro-sized channels are formed using semi-conductor fabrication techniques.

20. The apparatus as recited in claim 1 wherein said micro-sized channels are formed by laser etching, said channels having internal diameters in the range from 5 to 500 μ

m.

21. The apparatus as recited in claim 1 wherein said pressurized fluid delivery mechanism comprises means for applying pressure into opposed ends of rows and columns of orifices.

22. The apparatus as recited in claim 1 wherein said first plurality of orifices in said reservoir plate member comprises 96 orifices, said orifices arranged in an 8×

12 microtiter format.

23. The apparatus as recited in claim 22 wherein the center-to-center spacing of the orifices is 2.25, 4.5, or 9.0 mm.

24. The apparatus as recited in claim 1 further comprising means on said distribution plate member for introduction of liquid materials from an outer edge.

25. The apparatus as recited in claim 1 wherein each of said well members in said well plate member has a volume in the range of 5 to 2000 nanoliters.

26. The apparatus as recited in claim 25 wherein the volume is 100-800 nanoliters.

27. The apparatus as recited in claim 1 further comprising a sealing member positioned adjacent to the upper surface of said reservoir plate member.

28. A system for simultaneously processing multiple fluid samples comprising:

at least one fluid sample processing apparatus as set forth in claim 1; and

a robotic mechanism for automatically handling and processing fluid samples in said at least one fluid sample processing apparatus;

said robotic mechanism comprising a rack member for positioning of said at least one fluid sample processing apparatus thereon, a fluid transfer mechanism for injecting fluids into said fluid sample processing apparatus, and a controller for operating said fluid transfer mechanism.

29. The system as set forth in claim 28 further comprising a pressurized fluid delivery mechanism for selectively applying pressure to said fluid sample processing apparatus and thereby conveying fluids therethrough.

30. The system as set forth in claim 28 further comprising a vacuum mechanism for selectively applying a vacuum to said fluid sample processing apparatus and thereby conveying fluids therethrough.

31. The system as set forth in claim 28 wherein two fluid processing apparatuses are provided for simultaneously handling and processing by said robotic mechanism.

32. The system as set forth in claim 28 wherein said robotic mechanism is a Cartesian robot mechanism with at least one moveable arm member and further comprises a pressure pumping mechanism for distribution of fluid materials into and through said at least one fluid sample processing apparatus.

33. The system as set forth in claim 28 wherein said robotic mechanism is a Cartesian robot mechanism with at least one moveable arm member and further comprises a pressure pumping mechanism and a vacuum mechanism for distribution of fluid materials into and through said at least one fluid sample processing apparatus.

34. The system as set forth in claim 28 wherein said plurality of first orifices in said reservoir plate member comprises 96 orifices, said orifices arranged in an 8×

12 microtiter format.

35. The system as set forth in claim 28 wherein said plurality of first orifices in said reservoir plate member comprises 384 orifices, said orifices arranged in a 16×

24 row and column format.

36. The system as set forth in claim 28 wherein said plurality of first orifices in said reservoir plate member comprises 1536 orifices, said orifices arranged in a 32×

48 row and column format.

37. The system as set forth in claim 28 further comprising means for washing said reservoir, distribution and well plate members by application of pressure followed by evacuation by vacuum.

38. The system as set forth in claim 28 further comprising means to partially fill said well members in said well plate member.

39. The system as set forth in claim 28 further comprising a plurality of collection plate members for attachment to said at least one fluid sample processing apparatus, wherein liquids exhausted from said well plate member can be collected and apportioned.

40. The system as set forth in claim 28 further comprising means to concentrate materials in said well members.

41. The system as set forth in claim 40 wherein said means for concentrating materials comprises a flow of a gas material.

42. A fluid sample processing apparatus comprising:

a reservoir plate member;

a distribution plate member connected to said reservoir plate member; and

a well plate member connected to said distribution plate member;

said reservoir plate member having an upper surface and a lower surface and a first plurality of orifices in the upper surface for entry of liquids therein, and a plurality of second orifices on the lower surface for exhausting of liquids from said reservoir plate member, said first plurality of orifices being spatially oriented in across said first surface, said second plurality of orifices fluidically coupled to said first orifices, said second plurality of orifices arranged in a rectangular pattern directly adjacent to edges of said reservoir plate member;

a first plurality of micro-sized channels in said reservoir plate member for conveying liquids from said first plurality of orifices to said plurality of second orifices;

said distribution plate member having an upper surface and a lower surface and a plurality of layers and a plurality of third orifices in said upper surface of said distribution plate member, said third orifices being spatially arranged in a rectilinear pattern in alignment with said second plurality of orifices in said reservoir plate member in order to transfer liquids from said reservoir plate member to said distribution plate member, the rectangular pattern having a first pair of opposites sides and a second pair of opposite side, said first pair of opposite sides have corresponding with row inputs of said distribution plate, and said second pair of opposite sides corresponding with column inputs of said distribution plate;

a second plurality of micro-sized channels in said distribution plate member for fluid communication between the rectilinear array of orifices on the upper surface of distribution plate member and a plurality of fourth orifices on the lower surface of said distribution layer;

said well plate member having a plurality of well members therein, said well members having first openings in alignment with said plurality of fourth orifices in the lowermost layer of said distribution plate member.

43. A fluid sample processing apparatus comprising:

a reservoir plate member;

a distribution plate member connected to said reservoir plate member; and

a well plate member connected to said distribution plate member;

said reservoir plate member having an upper surface and a lower surface and a first plurality of orifices in the upper surface for entry of liquids therein, and a plurality of second orifices on the lower surface for exhausting of liquids from said reservoir plate member, said first and second plurality of orifices being spatially oriented;

a first plurality of micro-sized channels in said reservoir plate member for conveying liquids from said first plurality of orifices to said plurality of second orifices;

said distribution plate member having an upper surface and a lower surface and a plurality of third orifices in said upper surface of said distribution plate member, said third orifices being spatially arranged in alignment with said second plurality of orifices in said reservoir plate member in order to transfer liquids from said reservoir plate member to said distribution plate member;

a second plurality of micro-sized channels in said distribution plate member for fluid communication between the orifices on the upper surface of the distribution plate member and a plurality of fourth orifices on the lower surface of said distribution layer;

said well plate member having a plurality of well members therein for conducting chemical and biological events, said well members having first openings in alignment with said plurality of fourth orifices of said distribution plate member; and

a vacuum box mechanism for connected to said fluid sample processing apparatus for vacuum exhaustion of materials from said well plate member.

44. A fluid sample processing apparatus comprising:

a reservoir plate member;

a distribution plate member connected to said reservoir plate member; and

a well plate member connected to said distribution plate member;

said reservoir plate member having an upper surface and a lower surface and a first plurality of orifices in the upper surface for entry of liquids therein, and a plurality of second orifices on the lower surface for exhausting of liquids from said reservoir plate member, said first and second plurality of orifices being spatially oriented;

a first plurality of micro-sized channels in said reservoir plate member for conveying liquids from said first plurality of orifices to said plurality of second orifices;

said distribution plate member having an upper surface and a lower surface and a plurality of third orifices in said upper surface of said distribution plate member, said third orifices being spatially arranged in alignment with said second plurality of orifices in said reservoir plate member in order to transfer liquids from said reservoir plate member to said distribution plate member;

a second plurality of micro-sized channels in said distribution plate member for fluid communication between the orifices on the upper surface of the distribution plate member and a plurality of fourth orifices on the lower surface of said distribution layer;

said well plate member having a plurality of well members therein for conducting chemical and biological events, said well members having first openings in alignment with said plurality of fourth orifices of said distribution plate member; and

electrical spray means for exhaustion of liquid materials from said well members.

45. A fluid sample processing apparatus comprising:

a reservoir plate member;

a distribution plate member connected to said reservoir plate member; and

a well plate member connected to said distribution plate member;

said reservoir plate member having an upper surface and a lower surface and a first plurality of orifices in the upper surface for entry of liquids therein, and a plurality of second orifices on the lower surface for exhausting of liquids from said reservoir plate member, said first and second plurality of orifices being spatially oriented;

a first plurality of micro-sized channels in said reservoir plate member for conveying liquids from said first plurality of orifices to said plurality of second orifices;

said distribution plate member having an upper surface and a lower surface and a plurality of third orifices in said upper surface of said distribution plate member, said third orifices being spatially arranged in alignment with said second plurality of orifices in said reservoir plate member in order to transfer liquids from said reservoir plate member to said distribution plate member;

a second plurality of micro-sized channels in said distribution plate member for fluid communication between the orifices on the upper surface of the distribution plate member and a plurality of fourth orifices on the lower surface of said distribution layer;

said well plate member having a plurality of well members therein for conducting chemical and biological events, said well members having first openings in alignment with said plurality of fourth orifices of said distribution plate member; and

micro-sized valve means in said plurality of first openings in said well plate member.

46. A fluid sample processing apparatus comprising:

a reservoir plate member;

a distribution plate member connected to said reservoir plate member; and

a well plate member connected to said distribution plate member;

said reservoir plate member having an upper surface and a lower surface and a first plurality of orifices in the upper surface for entry of liquids therein, and a plurality of second orifices on the lower surface for exhausting of liquids from said reservoir plate member, said first and second plurality of orifices being spatially oriented;

a first plurality of micro-sized channels in said reservoir plate member for conveying liquids from said first plurality of orifices to said plurality of second orifices;

said distribution plate member having an upper surface and a lower surface and a plurality of third orifices in said upper surface of said distribution plate member, said third orifices being spatially arranged in alignment with said second plurality of orifices in said reservoir plate member in order to transfer liquids from said reservoir plate member to said distribution plate member;

a second plurality of micro-sized channels in said distribution plate member for fluid communication between the orifices on the upper surface of the distribution plate member and a plurality of fourth orifices on the lower surface of said distribution layer;

said well plate member having a plurality of well members therein for conducting chemical and biological events, said well members having first openings in alignment with said plurality of fourth orifices of said distribution plate member wherein said well members have second openings therein for exhaustion of materials from said well members, said second openings in said well members comprise a plurality of micro-sized valves.

47. The apparatus as recited in claim 46 wherein at least four micro-sized valves are provided.

48. The apparatus as recited in claim 46 wherein each of said micro-sized valves is tapered from a first diameter to a second diameter less than the first diameter.

49. A fluid sample processing apparatus comprising:

a reservoir plate member;

a distribution plate member connected to said reservoir plate member; and

a well plate member connected to said distribution plate member;

said reservoir plate member having an upper surface and a lower surface and a first plurality of orifices in the upper surface for entry of liquids therein, and a plurality of second orifices on the lower surface for exhausting of liquids from said reservoir plate member, said first and second plurality of orifices being spatially oriented;

a first plurality of micro-sized channels in said reservoir plate member for conveying liquids from said first plurality of orifices to said plurality of second orifices;

said distribution plate member having an upper surface and a lower surface and a plurality of third orifices in said upper surface of said distribution plate member, said third orifices being spatially arranged in alignment with said second plurality of orifices in said reservoir plate member in order to transfer liquids from said reservoir plate member to said distribution plate member;

a second plurality of micro-sized channels in said distribution plate member for fluid communication between the orifices on the upper surface of the distribution plate member and a plurality of fourth orifices on the lower surface of said distribution layer;

said well plate member having a plurality of well members therein for conducting chemical and biological events, said well members having first openings in alignment with said plurality of fourth orifices of said distribution plate member; and

a first sealing member positioned between said distribution plate member and said well plate member, said sealing member is an elastomeric member having a first plurality of openings positioned in alignment with said plurality of fourth orifices on said distribution plate member and a second plurality of openings positioned between said first plurality of openings, wherein when said sealing member is altered in cross-section, said elastomeric material can flow into said second openings.

50. A fluid sample processing apparatus comprising:

a reservoir plate member;

a distribution plate member connected to said reservoir plate member; and

a well plate member connected to said distribution plate member;

said reservoir plate member having an upper surface and a lower surface and a first plurality of orifices in the upper surface for entry of liquids therein, and a plurality of second orifices on the lower surface for exhausting of liquids from said reservoir plate member, said first and second plurality of orifices being spatially oriented;

a first plurality of micro-sized channels in said reservoir plate member for conveying liquids from said first plurality of orifices to said plurality of second orifices;

said distribution plate member having an upper surface and a lower surface and a plurality of third orifices in said upper surface of said distribution plate member, said third orifices being spatially arranged in alignment with said second plurality of orifices in said reservoir plate member in order to transfer liquids from said reservoir plate member to said distribution plate member;

a second plurality of micro-sized channels in said distribution plate member for fluid communication between the orifices on the upper surface of the distribution plate member and a plurality of fourth orifices on the lower surface of said distribution layer;

said well plate member having a plurality of well members therein for conducting chemical and biological events, said well members having first openings in alignment with said plurality of fourth orifices of said distribution plate member;

wherein said plurality of first orifices in said reservoir plate member comprises 384 orifices and said apparatus further comprises a second reservoir member attached to said reservoir plate member, said second reservoir member having 96 orifices on its upper surface and a plurality of fan-out channels therein communicating said 96 orifices to said 384 orifices on said reservoir plate member.

51. A fluid sample processing apparatus comprising:

a reservoir plate member;

a distribution plate member connected to said reservoir plate member; and

a well plate member connected to said distribution plate member;

said reservoir plate member having an upper surface and a lower surface and a first plurality of orifices in the upper surface for entry of liquids therein, and a plurality of second orifices on the lower surface for exhausting of liquids from said reservoir plate member, said first and second plurality of orifices being spatially oriented;

a first plurality of micro-sized channels in said reservoir plate member for conveying liquids from said first plurality of orifices to said plurality of second orifices;

said distribution plate member having an upper surface and a lower surface and a plurality of third orifices in said upper surface of said distribution plate member, said third orifices being spatially arranged in alignment with said second plurality of orifices in said reservoir plate member in order to transfer liquids from said reservoir plate member to said distribution plate member;

a second plurality of micro-sized channels in said distribution plate member for fluid communication between the orifices on the upper surface of the distribution plate member and a plurality of fourth orifices on the lower surface of said distribution layer;

said well plate member having a plurality of well members therein for conducting chemical and biological events, said well members having first openings in alignment with said plurality of fourth orifices of said distribution plate member;

wherein said plurality of first orifices in said reservoir plate member comprises 1536 orifices and said apparatus further comprises a second reservoir member attached to said reservoir plate member, said second reservoir member having 96 orifices on its upper surface and a plurality of fan-out channels therein communicating said 96 orifices to said 1536 orifices on said reservoir plate member.

52. A fluid sample processing apparatus comprising:

a reservoir plate member;

a distribution plate member connected to said reservoir plate member; and

a well plate member connected to said distribution plate member;

said reservoir plate member having an upper surface and a lower surface and a first plurality of orifices in the upper surface for entry of liquids therein, and a plurality of second orifices on the lower surface for exhausting of liquids from said reservoir plate member, said first and second plurality of orifices being spatially oriented;

a first plurality of micro-sized channels in said reservoir plate member for conveying liquids from said first plurality of orifices to said plurality of second orifices;

said distribution plate member having an upper surface and a lower surface and a plurality of third orifices in said upper surface of said distribution plate member, said third orifices being spatially arranged in alignment with said second plurality of orifices in said reservoir plate member in order to transfer liquids from said reservoir plate member to said distribution plate member;

a second plurality of micro-sized channels in said distribution plate member for fluid communication between the orifices on the upper surface of the distribution plate member and a plurality of fourth orifices on the lower surface of said distribution layer;

said well plate member having a plurality of well members therein for conducting chemical and biological events, said well members having first openings in alignment with said plurality of fourth orifices of said distribution plate member;

a plurality of magnets positioned adjacent to said well plate member for attracting magnetic particles in said well members.

53. A fluid sample processing apparatus comprising:

a reservoir plate member;

a distribution plate member connected to said reservoir plate member; and

a well plate member connected to said distribution plate member;

said reservoir plate member having an upper surface and a lower surface and a first plurality of orifices in the upper surface for entry of liquids therein, and a plurality of second orifices on the lower surface for exhausting of liquids from said reservoir plate member, said first and second plurality of orifices being spatially oriented;

a first plurality of micro-sized channels in said reservoir plate member for conveying liquids from said first plurality of orifices to said plurality of second orifices;

said distribution plate member having an upper surface and a lower surface and a plurality of third orifices in said upper surface of said distribution plate member, said third orifices being spatially arranged in alignment with said second plurality of orifices in said reservoir plate member in order to transfer liquids from said reservoir plate member to said distribution plate member;

a second plurality of micro-sized channels in said distribution plate member for fluid communication between the orifices on the upper surface of the distribution plate member and a plurality of fourth orifices on the lower surface of said distribution layer;

said well plate member having a plurality of well members therein for conducting chemical and biological events, said well members having first openings in alignment with said plurality of fourth orifices of said distribution plate member; and

a non-fluidic plate member having a plurality of light emitting detection elements therein.