Depositing fluid specimens on substrates, resulting ordered arrays, techniques for analysis of deposited arrays

• US 6,722,395 B2
• Filed: 05/21/2001
• Issued: 04/20/2004
• Est. Priority Date: 01/13/1998
• Status: Expired due to Term

• Current Assignee: Affymetrix, Inc. (Thermo Fisher Scientific Incorporated)
• Original Assignee: James W. Overbeck, Jean I. Montagu, Myles L. Mace, Peter Honkanen, Peter T. Flowers
• Inventors: Honkanen, Peter, Overbeck, James W., Montagu, Jean I., Mace, Myles L., Flowers, Peter T.
• Primary Examiner(s): Huson, Gregory L.
• Assistant Examiner(s): deVore, Peter
• Application Number:
  US09/862,177
• Publication Number:
  US 20020083998A1
• Time in Patent Office: 1,065 Days
• Field of Search: 141/1, 141/130, 141/279, 222/583, 422/100, 436/180, 118/401, 118/243, 118/263, 427/256
• US Class Current: 141/1
• 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 2219/00315 Microtiter plates
• CPC Class Codes: B01J 2219/00364 Pipettes
• CPC Class Codes: B01J 2219/00387 Applications using probes
• CPC Class Codes: B01J 2219/00527 Sheets
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/0059 Sequential processes
• CPC Class Codes: B01J 2219/00596 Solid-phase processes
• CPC Class Codes: B01J 2219/00605 the compounds being directly bound or immobilised to solid supports
• CPC Class Codes: B01J 2219/0061 The surface being organic
• CPC Class Codes: B01J 2219/00612 the surface being inorganic
• CPC Class Codes: B01J 2219/00617 by chemical means
• CPC Class Codes: B01J 2219/00619 using hydrophilic or hydrophobic regions
• CPC Class Codes: B01J 2219/00621 by physical means, e.g. trenches, raised areas
• CPC Class Codes: B01J 2219/00628 Ionic
• CPC Class Codes: B01J 2219/0063 Other, e.g. van der Waals forces, hydrogen bonding
• CPC Class Codes: B01J 2219/00637 by coating it with another layer
• CPC Class Codes: B01J 2219/00641 the porous medium being continuous, e.g. porous oxide substrates
• CPC Class Codes: B01J 2219/00659 Two-dimensional arrays
• CPC Class Codes: B01J 2219/00677 Ex-situ synthesis followed by deposition on the substrate
• CPC Class Codes: B01J 2219/00691 : using robots
• CPC Class Codes: B01J 2219/00722 : Nucleotides
• CPC Class Codes: B01J 2219/00725 : Peptides
• CPC Class Codes: B01J 2219/00729 : Peptide nucleic acids [PNA]
• CPC Class Codes: B01L 13/02 : for receptacle or instruments
• CPC Class Codes: B01L 3/0244 : using pins
• CPC Class Codes: B01L 3/0251 : Pin and ring type or pin in tube type dispenser
• CPC Class Codes: B82Y 30/00 : Nanotechnology for materials or surface science, e.g. nanocomposites
• CPC Class Codes: C40B 60/14 : for creating libraries
• CPC Class Codes: G01N 2035/1034 : Transferring microquantities of liquid
• CPC Class Codes: G01N 2035/1037 : Using surface tension, e.g. pins or wires
• CPC Class Codes: G01N 35/1065 : Multiple transfer devices
• CPC Class Codes: G02B 21/34 : Microscope slides, e.g. mounting specimens on microscope slides
• CPC Class Codes: Y10T 436/2575 : Volumetric liquid transfer

Abstract

For depositing fluid dots in an array, e.g., for microscopic analysis, a deposit device, e.g. a pin, cooperating with a fluid source defines a precisely sized drop of fluid of small diameter on a drop carrying surface. Transport mechanism positions the device precisely over the receiving surface and drive mechanism moves the deposit device toward and away from the surface. By repeated action, minute drops of fluid can be deposited precisely in a dense array, preferably under computer control. The drop-carrying surface shown has a diameter less than 375, preferably less than 300, preferably between about 15 and 250 micron, and is bound by a sharp rim that defines the perimeter of the fluid drop. The deposit device is compliant in the direction of deposition motion, e.g. by overcoming resistance of a resilient member. When depositing, the deposit device is laterally constrained to a reference position, e.g. by flexure mounting or the deposit device is mounted to displace from its mounting upon engagement with the receiving surface, and is subject to a lateral force or turning moment that engages the device with a lateral reference surface. A mobile-fluid storage device resupplies the deposit device along the array, e.g. in the immediate vicinity of the deposit locations. Mobile annular storage rings are lowered and raised to obtain a supply of fluid, or a mobile multiwell plate is used. Cleaning mechanism, sampling plans, and array products on microscope slides and fragile or soft membranes are disclosed as are many types of fluid and uses, e.g., in biotechnology, analysis and process control.

Claims

1. An apparatus for depositing fluid dots on a receiving surface in an array, comprising:

a deposit device cooperatively related a fluid source including biological material;

a drop-carrying element coupled to and displaced by the deposit device;

a fluid-retaining structure, co-operatively arranged with the drop-carrying element, constructed to retain fluid including biological material by surface tension, the fluid-retaining structure being constructed and shaped for at least partial immersion into a well including the biological material;

a transport mechanism for positioning the deposit device and the drop-carrying element at a precisely referenced position over the receiving surface; and

a drive mechanism for moving the drop-carrying element, relatively through the fluid-retaining structure to receive the fluid including the biological material, in deposition motion toward and away from the surface.

2. The apparatus of claim 1, wherein the fluid-retaining structure includes a ring constructed to retain the fluid including biological material by surface tension and enable movement of the drop-carrying element therethrough.

3. The apparatus of claim 2, wherein the deposit device includes a pin having the drop carrying elements formed by a tip arranged to linearly move with respect to and through a volume defined by the ring.

4. The apparatus of claim 2, wherein the well forms a portion of a well plate.

5. The apparatus of claim 4, wherein the well plate is a 96 well plate.

6. The apparatus of claim 4 further including a mechanism for transporting the well plate with respect to the receiving surface.

7. The apparatus of claim 1, wherein the fluid-retaining structure includes a helical structure constructed to retain the fluid including biological material by surface tension and enable movement of the drop-carrying element therethrough.

8. The apparatus of claim 7, wherein the receiving surface includes a rigid, smooth substrate.

9. The apparatus of claim 8, wherein the rigid, smooth substrate is a glass slide.

10. The apparatus of claim 7, wherein the receiving surface includes a porous membrane.

11. The apparatus of claim 7, wherein the receiving surface includes a nitrocellulose.

12. The apparatus of claim 11, wherein the receiving surface includes a cellulose acetate, polyvinylidine fluoride (PVDF) or nylon.

13. The apparatus of claim 12, wherein the receiving surface includes a gel.

14. The apparatus of claim 1, wherein the fluid-retaining structure includes a U-shaped structure constructed to retain the fluid including biological material by surface tension and enable movement of the drop-carrying element therethrough.

15. The apparatus of claim 1, wherein the fluid-retaining structure includes a structure having a square, hexagonal, rectangular or oval cross-section and being constructed to retain the fluid including biological material by surface tension and enable movement of the drop-carrying element therethrough.

16. The apparatus of claim 1, Wherein the fluid-retaining structure is formed by a member that has opposed or adjacent surfaces that can hold a mass of fluid between them by surface tension.

17. An apparatus for depositing fluid dots on a receiving surface in an array, comprising:

a multiplicity of deposit devices mounted for motion together in response to a common actuator, each said deposit device including a drop-carrying element;

a multiplicity of fluid-retaining structures associated with said multiplicity of deposit devices, each said fluid-retaining structure being constructed to retain fluid including biological material by surface tension, each said fluid-retaining structure being constructed for immersion inside a well to receive the fluid including biological material; and

a drive mechanism associated with said actuator constructed to move said multiplicity of deposit devices including said drop-carrying elements through said fluid-retaining structure to acquire a drop of the liquid onto each said drop-carrying element;

said drive mechanism being constructed to displace said deposit devices including said drop-carrying elements toward and away from the receiving surface for deposition.

18. The apparatus of claim 17, wherein said multiplicity of fluid-retaining structures is generally movable together with said multiplicity of deposit devices over an array of deposit locations.

19. The apparatus of claim 18, wherein said multiplicity of deposit devices and said multiplicity of fluid-retaining structures includes four deposit devices and associated four ring-like structures forming said fluid-retaining structures.

20. The apparatus of claim 18, wherein said multiplicity of fluid-retaining structures has a spacing and distribution corresponding to a spacing and distribution of said wells in a well plate.

21. The apparatus of claim 20, wherein the well plate is a 96 well plate.

22. The apparatus of claim 20 further including a mechanism for transporting said well plate with respect to the receiving surface.

23. The apparatus of claim 22, wherein the receiving surface is a surface of a glass slide.

24. The apparatus of claim 22, wherein the receiving surface includes a porous membrane.

25. The apparatus of claim 22, wherein the receiving surface includes a nitrocellulose.

26. The apparatus of claim 20, wherein each said fluid-retaining structure includes a circular-shaped member for said retention of liquid by surface tension.

27. The apparatus of claim 20, wherein each said fluid-retaining structure includes a U-shaped member for said retention of liquid by surface tension.

28. The apparatus of claim 20, wherein said fluid-retaining structure includes a helical member for said retention of liquid by surface tension.

29. The apparatus of claim 20, wherein said fluid-retaining structure includes a closed shape member for said retention of liquid by surface tension.

30. The apparatus of claim 20, wherein said fluid-retaining structure includes a partially closed shape member for said retention of liquid by surface tension.

31. The apparatus of claim 20, wherein said fluid-retaining structure is made of a material proving appropriate surface tension for retaining said liquid including biological material.

32. The apparatus of claim 20, wherein said fluid-retaining structure provides surface energy greater than about 2500 mN/m for retaining said liquid including biological material.

33. The apparatus of claim 18, wherein the receiving surface includes a rigid, smooth substrate.

34. The apparatus of claim 18, wherein the rigid, smooth substrate is a surface of a glass slide.

35. The apparatus of claim 18, wherein the receiving surface includes a porous membrane.

36. The apparatus of claim 18, wherein the receiving surface includes a nitrocellulose.