SYSTEMS AND METHODS FOR PREPARING AND ANALYZING LOW VOLUME ANALYTE ARRAY ELEMENTS

• US 20030096426A1
• Filed: 07/30/1999
• Published: 05/22/2003
• Est. Priority Date: 01/23/1997
• Status: Active Grant

• Current Assignee: Agena Bioscience Inc. (Mesa Laboratories Inc.)
• Original Assignee: Sequenom Incorporated (Laboratory Corporation Of America Holdings)
• Inventors: CANTOR, CHARLES R., KOSTER, HUBERT, LITTLE, DANIEL P., OʼDONNELL-MALONEY, MARYANNE J.
• Granted Patent: US 7,232,688 B2
• Time in Patent Office: Days
• US Class Current: 506/32
• 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

Methods for dispensing tools that can be employed to generate multi-element arrays of sample material on a substrate surface. The resulting substrates are also provided. 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 prepared sample arrays are passed 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 signals that are indicative of the composition of the sample material under analysis.

Claims

1. A method for forming an array of a sample material on a surface of a substrate comprising the steps of

providing a vesicle having an interior chamber containing a fluid,

disposing said vesicle adjacent to a first location on said surface of the substrate,

controlling said vesicle to eject from said chamber a nanoliter volume of the fluid to dispense said fluid at said first location of said surface of the substrate, and

moving said vesicle to a set of positions adjacent said surface of the substrate, whereby fluid is dispensed at each location of said set for forming said array of sample material.

2. A method according to claim 1, including the further step of

providing a substrate having wells formed on said surface of the substrate for defining locations for receiving said fluid ejected from said chamber.

3. A method according to claim 1, including the further steps of depositing a matrix material on a surface of said substrate.

4. A method according to claim 3, including the further step of waiting a predetermined period of time to allow the solvent of said matrix material to evaporate.

5. A method according to claim 4 wherein said step of ejecting a nanoliter volume of fluid includes the step of ejecting said fluid onto said evaporated matrix material to dissolve with said matrix material and to form a crystalline structure on said substrate surface.

6. A method according to claim 1 including the step of mixing an analyte material with a matrix material to form a solution, and filling said interior chamber with said solution.

7. A method according to claim 1, including the further step of providing said substrate with said array of sample material disposed thereon to a diagnostic tool for determining information representation of the composition of said sample material.

8. A method according to claim 7, wherein said step of providing said substrate to a diagnostic tool includes the step of

providing said substrate to a diagnostic tool having a mass spectrometer.

9. A method according to claim 1, wherein said step of providing a vesicle having an interior camber includes the step of providing a vesicle having a piezoelectric element for causing fluid to move through said chamber.

10. A method according to claim 9, wherein said step of moving said vesicle includes the step of rastering said vesicle across said surface of said substrate.

11. A method according to claim 1 wherein said step of providing a vesicle includes the step of providing a vesicle assembly having a plurality of vesicles arranged into a matrix for dispensing fluid to a first plurality of locations on said substrate surface.

12. A method according to claim 11 wherein said step of moving said vesicle array includes the step of determining an offset signal representative of a distance for moving said vesicle assembly to a location adjacent said first plurality of locations.

13. A method of according to claim 12 wherein said step of moving said vesicle assembly includes the step of moving said vesicle assembly over said surface of said substrate to form a matrix of locations having fluid ejected thereon.

14. A method according to claim 1, including the further step of drawing a wash fluid into said chamber to rinse said chamber.

15. A method according to claim 1, including the further step of contacting said vesicle to a source of fluid material for filling said chamber by capillary action.

16. A method according to claim 1, including the step of providing a substrate material comprising silicon.

17. A method according to claim 1, including the step of providing a substrate material comprising a metal material.

18. A method according to claim 1, including the step of providing a substrate material compromising a plastic material.

19. A method according to claim 1, including the step of providing a substrate material comprising a membrane.

20. A method according to claim 1, including the step of providing a substrate material comprising a polymeric material.

21. A method according to claim 1, including the step of providing a substrate material comprising metal-grafted polymers.

22. A method according to claim 1, including the step of providing a chemically functionalized substrate material.

23. A method according to claim 1, including the step of providing a substrate material functionalized with beads.

24. A method according to claim 1, including the step of providing a substrate material functionalized with a dendritic material.

25. A method for analyzing a material, comprising the steps of providing a vesicle suitable for carrying a fluid having said material therein, disposing said vesicle adjacent to a first location of a surface of a substrate,

controlling said vesicle to deliver a nanoliter volume of the fluid to provide a defined and controlled volume of said fluid at said first location of said surface of the substrate,

moving said vesicle to a second position adjacent to a second location on said surface of the substrate to dispense a defined and controlled volume of said material along an array of locations on said substrate surface, and

performing mass spectrometry analysis for said material at each location of said array.

26. A method according to claim 25 wherein said step of providing a vesicle, includes the step of mixing a matrix material and an analyte material to form said fluid material.

27. A method according to claim 25, including the steps of providing a vesicle having an interior chamber suitable for holding a fluid, and

filling said chamber with a matrix material and dispensing said matrix material to said array of locations.

28. A method according to claim 25 wherein said step of performing mass spectrometry includes the step of performing matrix assisted laser desorption ionization mass spectrometry.

29. A method according to claim 25 wherein said step of performing mass spectrometry includes the step of performing a time of flight mass spectrometry analysis.

30. A method according to claim 25 wherein said step of performing mass spectrometry includes the step of performing a fourier transform mass spectrometry analysis.

31. Apparatus for forming an array of a sample material on a surface of a substrate, comprising

vesicle having a distal end suitable for carrying a fluid thereon,

a movable arm having a distal portion mounted to said vesicle,

a controller for moving said arm to dispose said vesicle adjacent to at first location on said surface of the substrate and for controlling said vesicle to provide a nanoliter volume of the fluid at said first location of said surface of the substrate, and

a diagnostic tool for analyzing said material to generate a composition signal representative of the chemical composition of said material.

32. Apparatus according to claim 31 wherein said vesicle comprises a solid shaft of material.

33. Apparatus according to claim 31 wherein said vesicle comprises an interior chamber suitable for carrying a fluid material.

34. Apparatus according to claim 31 wherein said vesicle comprises a chamber and a transducer element for ejecting from said chamber.

35. Apparatus according to claim 31 wherein said diagnostic tool includes a mass spectrometer.

36. A substrate having a surface carrying an array of matrix material and formed according to a process comprising the steps of

providing a vesicle suitable for transferring nanovolumes of fluid containing a matrix material,

disposing said vesicle adjacent to a first location on said surface of the substrate,

controlling said vesicle to deliver a volume of the fluid to said first location of said surface of the substrate, and

moving said vesicle to a set of positions adjacent to the surface of the substrate and delivering a nanovolume of fluid at each location of said set to form an array of matrix material.

37. A substrate according to claim 36 having wells disposed on said surface.

38. A substrate according to claim 37 wherein said surface is pitted.

39. A substrate according to claim 37 wherein said wells have a rough interior surface.