Self-encoding sensor with microspheres

• US 8,030,094 B2
• Filed: 07/12/2010
• Issued: 10/04/2011
• Est. Priority Date: 10/06/1997
• Status: Expired due to Fees

• Current Assignee: Trustees of Tufts College
• Original Assignee: Trustees of Tufts College
• Inventors: Walt, David R., Dickinson, Todd A.
• Primary Examiner(s): GABEL, GAILENE
• Application Number:
  US12/834,422
• Publication Number:
  US 20100279880A1
• Time in Patent Office: 449 Days
• Field of Search: 435/6, 435/7.1, 435/7.92, 435/91, 435/287.2, 435/288.4, 436/19, 436/164, 436/171, 436/172, 436/518, 436/523, 422/55, 422/68.1, 422/82.05, 422/82.06, 422/82.07, 422/82.08, 422/91
• US Class Current: 436/523
• CPC Class Codes: B01J 2219/00317 Microwell devices, i.e. having large numbers of wells
• CPC Class Codes: B01J 2219/0045 using optical fibres
• CPC Class Codes: B01J 2219/00466 in a slurry
• CPC Class Codes: B01J 2219/005 Beads
• CPC Class Codes: B01J 2219/00524 in the shape of fiber bundles
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/00648 by the use of solid beads
• CPC Class Codes: B01J 2219/00659 Two-dimensional arrays
• CPC Class Codes: C12Q 1/682 Signal amplification
• CPC Class Codes: C12Q 1/6834 Enzymatic or biochemical coupling of nucleic acids to a solid phase
• CPC Class Codes: C40B 60/14 for creating libraries
• CPC Class Codes: G01N 21/6428 Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" in vivo A61B5/00; immunoassay G01N33/53
• CPC Class Codes: G01N 21/6452 Individual samples arranged in a regular 2D-array, e.g. multiwell plates
• CPC Class Codes: G01N 21/7703 using reagent-clad optical fibres or optical waveguides using measurement of total internal reflection or attenuated total reflection G01N21/552; optical fibres or waveguides per se G02B
• CPC Class Codes: G01N 2201/0846 Fibre interface with sample, e.g. for spatial resolution
• CPC Class Codes: G01N 33/0031 comprising two or more sensors, e.g. a sensor array electrochemical electrode arrays G01N27/27
• CPC Class Codes: G01N 33/54313 the carrier being characterised by its particulate form
• CPC Class Codes: Y10T 436/101666 Particle count or volume standard or control [e.g., platelet count standards, etc.]
• CPC Class Codes: Y10T 436/109163 Inorganic standards or controls

Abstract

A microsphere-based analytic chemistry system is disclosed in which self-encoding microspheres having distinct characteristic optical response signatures to specific target analytes may be mixed together while the ability is retained to identify the sensor type and location of each sensor in a random dispersion of large numbers of such sensors in a sensor array using an optically interrogatable encoding scheme. An optical fiber bundle sensor is also disclosed in which individual microsphere sensors are disposed in microwells at a distal end of the fiber bundle and are optically coupled to discrete fibers or groups of fibers within the bundle. The identities of the individual sensors in the array are self-encoded by exposing the array to a reference analyte while illuminating the array with excitation light energy. A single sensor array may carry thousands of discrete sensing elements whose combined signal provides for substantial improvements in sensor detection limits, response times and signal-to-noise ratios.

Claims

1. A method for increasing the signal-to-noise ratio in a sensor array, said method comprising:

a) providing a sensor array having a plurality of subgroups of sensor elements, wherein each of the sensor elements of a subgroup comprises the same bioactive agent;

b) providing an analyte to said sensor array, such that said analyte is accessible to said sensor elements;

c) detecting an optical response signal from a first sensor element and a second sensor element of the same subgroup, wherein said first sensor element and said second sensor element interact with said analyte to produce said response signal, and wherein the response signals from said first sensor element and said second sensor element are separately detected; and

d) combining the optical response signals from said first sensor element and said second sensor element, thereby increasing the signal-to-noise ratio in the sensor array.

2. The method of claim 1, wherein the step of combining comprises summing the optical response signals from said first sensor element and said second sensor element.

3. The method of claim 1 further comprising, prior to step d), adjusting the baseline of an optical response signal of a sensor element.

4. The method of claim 1, wherein said sensor elements comprise microspheres.

5. The method of claim 1, wherein said sensor elements comprise oligonucleotides.

6. The method of claim 1, wherein the first sensor element and the second sensor element each comprise an oligonucleotide having the same sequence.

7. The method of claim 1, wherein the analyte comprises an oligonucleotide.

8. The method of claim 1, wherein the signal-to-noise ratio is increased by a factor of at least 10.

9. The method of claim 1, wherein an analyte detection limit is reduced by a factor of at least 100.

10. The method of claim 1, wherein said sensor array comprises microspheres distributed on a substrate.

11. The method of claim 1, wherein said sensor array comprises microspheres distributed in wells.

12. The method of claim 1, wherein said sensor array comprises a planar surface.

13. The method of claim 1, wherein said sensor array comprises a fiber optic bundle.

14. The method of claim 1 further comprising identifying the location of one or more sensor elements within each sensor subgroup.

15. A method for amplifying a response signal of a sensor array, said method comprising:

a) providing a sensor array having a plurality of subgroups of sensor elements, wherein each of the sensor elements of a subgroup comprises the same bioactive agent;

b) providing analytes to said sensor array, such that said analyte is accessible to said sensor elements;

c) detecting an optical response signal from a first sensor element and a second sensor element of the same subgroup, wherein said first sensor element and said second sensor element interact with said analyte to produce said response signal, and wherein the response signals from said first sensor element and said second sensor element are separately detected; and

d) combining the optical response signals from said first sensor element and said second sensor element, thereby amplifying said response signal.

16. The method of claim 15, wherein the step of combining comprises summing the optical response signals from said first sensor element and said second sensor element.

17. The method of claim 15 further comprising, prior to step d), adjusting the baseline of an optical response signal of a sensor element.

18. The method of claim 15, wherein said sensor elements comprise microspheres.

19. The method of claim 15, wherein said sensor elements comprise oligonucleotides.

20. The method of claim 15, wherein the first sensor element and the second sensor element each comprise an oligonucleotide having the same sequence.

21. The method of claim 15, wherein the analytes comprise oligonucleotides.

22. The method of claim 15, wherein the response signal is amplified by a factor of at least 50.

23. The method of claim 15, wherein an analyte detection limit is reduced by a factor of at least 100.

24. The method of claim 15, wherein said sensor array comprises microspheres distributed on a substrate.

25. The method of claim 15, wherein said sensor array comprises microspheres distributed in wells.

26. The method of claim 15, wherein said sensor array comprises a planar surface.

27. The method of claim 15, wherein said sensor array comprises a fiber optic bundle.

28. The method of claim 15 further comprising identifying the location of one or more sensor elements within each sensor subgroup.