CA2382436A1 - Methods for improving signal detection from an array - Google Patents

Methods for improving signal detection from an array Download PDF

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CA2382436A1
CA2382436A1 CA002382436A CA2382436A CA2382436A1 CA 2382436 A1 CA2382436 A1 CA 2382436A1 CA 002382436 A CA002382436 A CA 002382436A CA 2382436 A CA2382436 A CA 2382436A CA 2382436 A1 CA2382436 A1 CA 2382436A1
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substrate
microspheres
discrete
composition according
sites
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CA2382436C (en
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Todd Dickinson
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Illumina Inc
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/6452—Individual samples arranged in a regular 2D-array, e.g. multiwell plates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00279—Features relating to reactor vessels
    • B01J2219/00306—Reactor vessels in a multiple arrangement
    • B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
    • B01J2219/00315—Microtiter plates
    • B01J2219/00317—Microwell devices, i.e. having large numbers of wells
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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    • B01J2219/00277—Apparatus
    • B01J2219/00497—Features relating to the solid phase supports
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    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J2219/00596—Solid-phase processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
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    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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    • B01J2219/00614—Delimitation of the attachment areas
    • B01J2219/00621—Delimitation of the attachment areas by physical means, e.g. trenches, raised areas
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B01J2219/00623—Immobilisation or binding
    • B01J2219/00626—Covalent
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00639—Making arrays on substantially continuous surfaces the compounds being trapped in or bound to a porous medium
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
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    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00646—Making arrays on substantially continuous surfaces the compounds being bound to beads immobilised on the solid supports
    • B01J2219/00648—Making arrays on substantially continuous surfaces the compounds being bound to beads immobilised on the solid supports by the use of solid beads
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
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    • B01J2219/00583—Features relative to the processes being carried out
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    • B01J2219/00659—Two-dimensional arrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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    • B01J2219/00702—Processes involving means for analysing and characterising the products
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J2219/00718—Type of compounds synthesised
    • B01J2219/0072—Organic compounds
    • B01J2219/00722—Nucleotides
    • C—CHEMISTRY; METALLURGY
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    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C40B40/06—Libraries containing nucleotides or polynucleotides, or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B60/00—Apparatus specially adapted for use in combinatorial chemistry or with libraries
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    • C40—COMBINATORIAL TECHNOLOGY
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    • C40B70/00—Tags or labels specially adapted for combinatorial chemistry or libraries, e.g. fluorescent tags or bar codes

Abstract

Methods of improving signal detection in microsphere array sensors are described, together with methods for background subtraction in an array. This effect can be achieved using arrays with wells with different shapes, or surfaces coated with reflective or selectively absorptive coatings. In addition, the array includes a signal transducer element.

Claims (46)

1. A composition comprising:
a) a substrate with a surface comprising discrete sites;
b) a reflective coating on said surface; and c) a population of microspheres distributed on said substrate said microspheres comprising at least a first and a second subpopulation.
2. A composition according to claim 1 wherein at least one subpopulation comprises a bioactive agent.
3. A composition according to claim 1, wherein said substrate comprises a first and a second surface, wherein said first surface comprises said discrete sites, said reflective coating on said second surface, said population of microspheres distributed on said first surface.
4. A composition according to claim 1 or claim 3, wherein said substrate is a fiber optic bundle.
5. A composition according to claim 4, wherein said fiber optic bundle comprises wells comprising said microspheres.
6. A composition according to claim 1 or claim 3, wherein said substrate is selected from the group consisting of glass and plastic.
7. A composition according to claim 1 or claim 3, wherein said reflective coating is a metal.
8. A composition according to claim 7, wherein said metal is selected from the group consisting of gold, silver, chromium, platinum and indium tin oxide.
9. A composition according to claim 1 or claim 3 wherein said reflective coating is a dielectric coating.
10. A composition according to claim 1 or claim 3, wherein said reflective coating selectively absorbs certain wavelengths.
11. A method of making a reflective array comprising:
a) providing a substrate with a surface comprising discrete sites:
b) applying to said surface a coating of reflective material; and c) distributing microspheres on said surface.
12. A method according to claim 11 wherein said microspheres comprise a bioactive agent.
13. A method according to claim 11, wherein said substrate comprises a first and a second surface, wherein said first surface comprises discrete sites, said reflective material on said second surface and said microspheres distributed on said first surface.
14. A method comprising:
a) providing a pre-formed unitary fiber optic bundle comprising a proximal and a distal end, said distal end comprising plurality of discrete sites comprising a population of microspheres, said population comprising at least first and second subpopulations; and c) imaging said fiber optic bundle from said distal end.
15. A method according to claim 14, wherein a reflective coating is present on said distal end of said fiber optic bundle.
16. A method according to claim 14, wherein a reflective coating is present on said proximal end of said fiber optic bundle.
17. An array composition comprising a substrate with a surface comprising discrete sites comprising alternatively shaped wells.
18. A composition according to claim 17, wherein the wall angle of said alternatively shaped wells is a sloped wall angle.
19. A composition according to claim 17, wherein said alternatively shaped wells contain a rounded wall interior.
20. A composition according to claim 17, wherein at least one of said alternatively shaped wells is a geometrically shaped well.
21. A composition according to claim 20, wherein said geometrically shaped well has a cross section selected from the group consisting of a square, a hexagon, a star, a triangle, a pentagon and an octagon.
22. A composition according to claim 17, further comprising a population of microspheres distributed in said wells.
23. A composition according to claim 22, wherein said population comprises at least first and second subpopulations, each of said subpopulations comprising a bioactive agent.
24. A composition according to claim 17, wherein said substrate is a transparent substrate comprising a first and a second surface, said first surface comprising discrete sites, and a reflective coating on said second surface.
25. A method comprising:
a) providing a substrate with a plurality of discrete sites, said sites comprising:
i) alternatively shaped wells; and ii) a population of microspheres, said population comprising at least first and second subpopulations; and b) imaging said substrate.
26. A method according to claim 25 wherein at least one of said subpopulations comprises a bioactive agent.
27. A method according to claim 25, wherein said alternatively shaped wells are geometrically shaped wells.
28. A method according to claim 27, wherein the cross section of said geometrically shaped wells is selected from the group consisting of a square, a hexagon, a star, a triangle, a pentagon and an octagon.
29. An array composition comprising:
a) a substrate with a surface comprising discrete sites; and b) a population of microspheres distributed on said substrate, wherein said microspheres comprise:
i) a bioactive agent; and ii) a signal transducer element.
30. A composition according to claim 29, wherein said signal transducer element is a nucleotide intercalator.
31. A composition according to claim 29, wherein said signal transducer element is a fluorophore.
32. A method of detecting a non-labeled target analyte in a sample comprising:
a) providing a substrate with a plurality of discrete sites;

b) distributing on said sites a population of microspheres comprising:
i) a bioactive agent;
ii) a signal transducer element;
c) contacting said substrate with said sample, whereby upon binding of said target analyte to said bioactive agent, a signal from signal transducer element is altered as an indication of the presence of said target analyte.
33. A method of detecting a chiral molecule in a sample comprising:
a) providing a substrate with a surface comprising:
i) at least first and second discrete sites; and ii) at least first and second bioactive agents attached to said first and second discrete sites respectively;
b) contacting said substrate with said sample;
c) illuminating said substrate with polarized light; and d) detecting rotation of said light in at least one of said first and second discrete sites as an indication of the presence of said chiral molecule.
34. A method according to claim 33, wherein said chiral molecule is DNA.
35. A method according to claim 33, wherein said first and second bioactive agents are chiral molecules.
36. A method according to claim 35, wherein said first and second bioactive agents are attached to said sites via first and second microspheres, respectively, said microspheres distributed at said sites.
37. A method of determining the location of a microsphere in an array comprising:
a) providing a substrate with a first surface comprising at least a first and a second discrete site, said first discrete site comprising a microsphere, said second discrete site not comprising a microsphere;
b) illuminating said substrate; and c) detecting illumination of said substrate, whereby reduced illumination at said first discrete site relative to said second discrete site provides an indication of the presence of said first microsphere in said first discrete site.
38. A method according to claim 37, wherein said substrate is a fiber optic bundle and said discrete sties are wells, wherein said first surface is the distal end of the fiber optic bundle, and said detecting is with a detector at the proximal end of the fiber optic bundle.
39. A method of increasing signal output from an array, said method comprising a) providing a substrate with a surface comprising:
i) at least first and second discrete sites; and ii) at least first and second labels attached to said first and second discrete sites respectively;
b) cooling said substrate to at least below room temperature; and c) detecting a signal from said first and second labels, whereby said signal is increased relative to a signal obtained from a substrate that is not cooled.
40. A method according to claim 39, wherein substrate is cooled to at least 0°F.
41. A method for background signal subtraction in an array comprising:
a) providing a substrate with a surface comprising:
i) at least first and second discrete sites; and ii) at least first and second labels attached to said first and second discrete sites respectively;
b) detecting the signal from said first and second discrete sites in a plurality of different emissions; and c) subtracting the lowest signal from each of said first and second discrete sites from the remaining signals from said first and second discrete sites, respectively.
42. A method of correcting image non-uniformity comprising:
a) providing a substrate with a surface comprising:
i) at least first and second discrete sites;
ii) at least first and second labels attached to said first and second discrete sites respectively; and iii) at least a first internal reference point of known signal intensity;
b) detecting a first and second signal from said first and second labels, respectively;
c) detecting a signal from said internal reference point; and d) determining the variation between said signal from said internal reference point and the known signal intensity of said internal reference point as an indication of said image non-uniformity.
43. A method according to claim 42 further comprising:
e) correcting said first and second signal from said first and second labels, respectively, by an amount equal to the variation between said signal from said internal reference point and the known signal intensity of said internal reference point.
44. A method according to claim 42 wherein said first internal reference point is a microsphere distributed on a site.
45. A method according to claim 42, wherein said first and second labels are attached to said sites via first and second microspheres, respectively, said microspheres distributed at said sites.
46. A method according to claim 45, wherein each of said microspheres comprises an internal reference point of known signal intensity.
CA2382436A 1999-08-30 2000-08-30 Methods for improving signal detection from an array Expired - Lifetime CA2382436C (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US15148399P 1999-08-30 1999-08-30
US60/151,483 1999-08-30
US15166899P 1999-08-31 1999-08-31
US60/151,668 1999-08-31
PCT/US2000/023830 WO2001018524A2 (en) 1999-08-30 2000-08-30 Methods for improving signal detection from an array

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CA2382436C CA2382436C (en) 2011-05-17

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EP (1) EP1212599A2 (en)
AU (1) AU2246601A (en)
CA (1) CA2382436C (en)
WO (1) WO2001018524A2 (en)

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