Systems and methods for preparing and analyzing low volume analyte array elements

• US 7,285,422 B1
• Filed: 01/23/1997
• Issued: 10/23/2007
• Est. Priority Date: 01/23/1997
• Status: Expired due to Fees

• Current Assignee: Agena Bioscience Inc. (Mesa Laboratories Inc.)
• Original Assignee: Sequenom Incorporated (Laboratory Corporation Of America Holdings)
• Inventors: Little, Daniel P., Cantor, Charles R., O'Donnell-Maloney, Maryanne J., Koster, Hubert
• Primary Examiner(s): Gakh; Yelena G.
• Application Number:
  US08/786,988
• Time in Patent Office: 3,925 Days
• Field of Search: 436/43, 436/49, 436/54, 436/164, 436/165, 436/166, 436/171, 436/174, 436/179, 436/180, 436/807, 436/809, 436/173, 436/86, 422/63, 422/65, 422/68.1, 422/81, 422/82.05, 422/100, 222/420
• US Class Current: 436/180
• 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 2219/00317 Microwell devices, i.e. having large numbers of wells
• CPC Class Codes: B01J 2219/00378 Piezoelectric or ink jet dispensers
• CPC Class Codes: B01J 2219/00387 Applications using probes
• CPC Class Codes: B01J 2219/00468 by manipulation of individual beads
• CPC Class Codes: B01J 2219/00497 Features relating to the solid phase supports
• CPC Class Codes: B01J 2219/005 Beads
• CPC Class Codes: B01J 2219/00504 Pins
• CPC Class Codes: B01J 2219/00511 Walls of reactor vessels
• CPC Class Codes: B01J 2219/0052 in the shape of elongated tubes
• CPC Class Codes: B01J 2219/00527 Sheets
• CPC Class Codes: B01J 2219/00585 Parallel 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 2219/00621 by physical means, e.g. trenches, raised areas
• 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 2219/00648 : by the use of solid beads
• CPC Class Codes: B01J 2219/00659 : Two-dimensional arrays
• 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: B01L 3/0244 : using pins
• CPC Class Codes: B01L 3/0262 : using touch-off at substrate or container
• CPC Class Codes: B01L 3/0268 : using pulse dispensing or spraying, eg. inkjet type, piezo actuated ejection of droplets from capillaries
• CPC Class Codes: C07B 2200/11 : Compounds covalently bound to a solid support
• CPC Class Codes: C07F 9/2408 : of hydroxyalkyl compounds
• CPC Class Codes: C07F 9/2429 : of arylalkanols
• CPC Class Codes: C07H 21/00 : Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• 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 60/14 : for creating libraries
• CPC Class Codes: G01N 2035/1037 : Using surface tension, e.g. pins or wires
• CPC Class Codes: G01N 2035/1069 : by adjusting the spacing between multiple probes of a single transferring head
• CPC Class Codes: G01N 35/1067 : for transfer to or from containers having different spacing
• CPC Class Codes: G01N 35/1074 : arranged in a two-dimensional array
• CPC Class Codes: H01J 49/0418 : for laser desorption, e.g. matrix-assisted laser desorption/ionisation [MALDI] plates or surface enhanced laser desorption/ionisation [SELDI] plates
• CPC Class Codes: Y10T 428/26 : Web or sheet containing structurally defined element or component, the element or component having a specified physical dimension
• CPC Class Codes: Y10T 428/31678 : Of metal
• CPC Class Codes: Y10T 428/31855 : Of addition polymer from unsaturated monomers
• CPC Class Codes: Y10T 436/119163 : with aspirator of claimed structure
• CPC Class Codes: Y10T 436/24 : Nuclear magnetic resonance, electron spin resonance or other spin effects or mass spectrometry
• CPC Class Codes: Y10T 436/25 : including sample preparation
• CPC Class Codes: Y10T 436/2575 : Volumetric liquid transfer

Abstract

The invention provides methods for dispensing tools that can be employed to generate multi-element arrays of sample material on a substrate surface. The substrates surfaces can be flat or geometrically altered to include wells of receiving material. The tool can dispense a spot of fluid to a substrate surface by spraying the fluid from the pin, contacting the substrate surface or forming a drop that touches against the substrate surface. The tool can form an array of sample material by dispensing sample material in a series of steps, while moving the pin to different locations above the substrate surface to form the sample array. The invention then passes the prepared sample arrays to a plate assembly that disposes the sample arrays for analysis by mass spectrometry. To this end, a mass spectrometer is provided that generates a set of spectra signal which can be understood as indicative of the composition of the sample material under analysis.

Claims

1. A process for preparing a substrate having an array of spots having matrix for matrix-assisted laser-desorption ionization (MALDI) mass spectrometry and no analyte, which comprises:

(a) depositing a defined and controlled 0.2 to 20 nanoliter volume of a solution comprising 3-hydroxypicolinic acid matrix, an evaporating solvent and no analyte at a plurality of discrete locations on the surface of a substrate by an automated dispenser; and

(b) evaporating the solvent, thereby forming an array of spots on the surface of the substrate comprising the matrix and no analyte.

2. The process of claim 1, wherein the substrate comprises material selected from the group consisting of silica, glass, cellulose, silicon, metal, plastic, polymer and metal-grafted polymer.

3. The process of claim 2, wherein the substrate comprises silicon.

4. The process of claim 2, wherein the substrate comprises a metal.

5. The process of claim 2, wherein the substrate comprises a plastic.

6. The process of claim 2, wherein the substrate comprises a metal-grafted polymer.

7. The process of claim 1, wherein the substrate is selected from the consisting of a flat surface, a flat surface with pits, a solid or porous bead, a membrane or a pin.

8. The process of claim 7, wherein the substrate comprises a flat surface.

9. The process of claim 7, wherein the substrate comprises a membrane.

10. The process of claim 1, wherein the substrate is chemically functionalized.

11. The process of claim 10, wherein the substrate is chemically functionalized with beads.

12. The process of claim 10, wherein the substrate is chemically functionalized with a dendritic material.

13. The process of claim 1, wherein the substrate is a chip.

14. The process of claim 13, wherein the substrate is a silicon chip.

15. The process of claim 1, wherein each spot is a flat disk.

16. The process of claim 1, wherein the spot size is defined by square dimensions of 800 micrometers by 800 micrometers or less.

17. The process of claim 1, wherein the spot size is defined by square dimensions of 450 micrometers by 450 micrometers or less.

18. The process of claim 1, wherein each spot consists essentially of the matrix after the solvent has evaporated.

19. The process of claim 18, wherein each spot consists of the matrix after the solvent has evaporated.

20. The process of claim 1, wherein the solvent comprises water.

21. The process of claim 20, wherein the solvent is water.

22. The process of claim 1, wherein the solvent comprises CH₃CN.

23. The process of claim 22, wherein the solvent is 50% CH₃CN.

24. The process of claim 1, wherein the solution comprising the matrix is a saturated matrix solution.

25. The process of claim 1, wherein the solution comprising the matrix is a diluted matrix solution.

26. The process of claim 1, wherein the automated dispenser comprises a vesicle having a chamber and a transducer element for ejecting fluid from the chamber.

27. The process of claim 26, wherein the transducer element is selected from the group consisting of piezoelectric, electric, electrorestrictive, magnetorestrictive, electrochemical transducers and the like.

28. The process of claim 27, wherein the transducer element is a piezoelectric transducer.

29. The process of claim 1, wherein the automated dispenser deposits the solution without touching the surface of the substrate.

30. The process of claim 1, wherein the automated dispenser comprises vesicle that comprises a pin having a chamber of sufficient narrow bore to allow the chamber to at least partially fill with a solution by capillary action.

31. The process of claim 1, wherein the automated dispenser deposits the solution by contacting the surface of the substrate.

32. The process of claim 1, wherein the automated dispenser comprises a vesicle that comprises a solid shaft of material.

33. The process of claim 1, wherein the automated dispenser comprises a vesicle that is rastered over the surface of the substrate.

34. The process of claim 1, wherein the automated dispenser comprises a plurality of vesicles in an array.