Fiber optic sensor with encoded microspheres

• US 6,023,540 A
• Filed: 03/14/1997
• Issued: 02/08/2000
• Est. Priority Date: 03/14/1997
• Status: Expired due to Term

• Current Assignee: Trustees of Tufts College
• Original Assignee: Trustees of Tufts College
• Inventors: Walt, David R., Michael, Karri Lynn
• Primary Examiner(s): NGO, HUNG NHAT
• Application Number:
  US08/818,199
• Time in Patent Office: 1,061 Days
• Field of Search: 385/12, 385/13, 385/31, 385/33, 385/38, 385/147, 385/901, 385/35, 359/368, 356/236, 435/808, 436/164, 436/172, 436/800, 436/805, 250/556
• US Class Current: 385/12
• CPC Class Codes: B01J 2219/00317 Microwell devices, i.e. having large numbers of wells
• 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 2219/00596 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 2219/00626 Covalent
• 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 2219/00648 by the use of solid beads
• 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 2219/00704 integrated with the reactor apparatus
• CPC Class Codes: B01J 2219/00725 Peptides
• CPC Class Codes: B01J 2219/0074 Biological products
• CPC Class Codes: B82Y 30/00 Nanotechnology for materials or surface science, e.g. nanocomposites
• CPC Class Codes: C12Q 1/6837 : using probe arrays or probe chips C12Q1/6874 takes precedence
• CPC Class Codes: C40B 40/10 : Libraries containing peptides or polypeptides, or derivatives thereof
• CPC Class Codes: G01N 15/1433 : using image recognition
• CPC Class Codes: G01N 15/1456 : without spatial resolution of the texture or inner structure of the particle, e.g. processing of pulse signals
• CPC Class Codes: G01N 15/1459 : the analysis being performed on a sample stream
• CPC Class Codes: G01N 15/1468 : with spatial resolution of the texture or inner structure of the particle
• CPC Class Codes: G01N 2015/1438 : Using two lasers in succession
• CPC Class Codes: G01N 2021/6484 : Optical fibres
• CPC Class Codes: G01N 2021/7786 : Fluorescence
• CPC Class Codes: G01N 2035/0097 : monitoring reactions as a function of time
• 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 33/54346 : Nanoparticles
• CPC Class Codes: Y10S 359/90 : Methods
• CPC Class Codes: Y10S 435/808 : Optical sensing apparatus

Abstract

A microsphere-based analytic chemistry system is disclosed in which microspheres carrying different chemical functionalities may be mixed together while the ability is retained to identify the functionality on each bead using an optically interrogatable encoding scheme. An optical fiber bundle sensor is also disclosed in which the separate microspheres may be optically coupled to discrete fibers or groups of fibers within the bundle. The functionalies are encoded on the separate microspheres using fluorescent dyes and then affixed to wells etched in the end of the bundle. Thus, a single sensor may carry thousands of chemistries. Only those microspheres exhibiting reactions then need to be decoded to identify the corresponding functionality.

Claims

1. A chemical analysis method, comprising

preparing separate subpopulations of beads, each subpopulation carrying chemical functionalities that change optical signatures of the beads in the presence of targeted analytes;

encoding optical signature of the beads in each subpopulation with a description of the chemical functionalities carried by that subpopulation;

combining the subpopulations to produce a system;

applying the system;

detecting changes in the optical signatures indicative of a presence of the targeted analytes; and

decoding optical signature of the beads to identify the chemical functionalities.

2. The method described in claim 1, wherein encoding the optical signatures with the chemical functionalities comprises doping the beads with fluorescent dyes.

3. The method described in claim 1, wherein encoding the optical signatures with chemical functionalities comprises attaching encoding dyes to the beads.

4. The method described in claim 1, wherein encoding the optical signatures with the chemical functionalities comprises controlling a ratio of at least two dyes carried by each bead.

5. The method described in claim 1, further comprising:

encoding the beads with the chemical functionalities by entrapping dyes within or attaching dyes to the beads; and

applying the chemical functionalities to the beads.

6. The method described in claim 1, further comprising enabling the chemical functionalities to produce an optically active species in the presence of targeted analytes to change the optical signature.

7. The method described in claim 1, further comprising changing the optical signature by the presence or absence of a fluorescent signal from the beads.

8. The method described in claim 1, further comprising enabling the chemical functionalities to hybridize.

9. An analytic chemistry sensor, comprising:

a bundle of optical fibers;

a population of beads carrying chemical functionalities at a distal end of the fiber optic bundle, light from individual bead being coupled into separate or groups of separate fibers of the bundle for transmission to the proximal end of the bundle.

10. The sensor described in claim 9, wherein each one of the beads is located within separate wells formed at terminal ends of optical fibers of the bundle.

11. The sensor described in claim 10, wherein the wells are formed by anisotropic etching of the cores of the optical fibers with respect to the cladding.

12. The sensor described in claim 9, further comprising a light source for exciting optically active chemicals bound to the chemical functionalities.

13. The sensor described in claim 9, wherein the population of beads includes separate subpopulations, each subpopulation carrying a different chemical functionality and an optically interrogatable code descriptive of the chemical functionality.

14. The sensor described in claim 13, further comprising a light source for exciting optically active chemicals bound to the chemical functionalities.

15. The sensor described in claim 13, wherein code of each subpopulation comprises fluorescent dyes.

16. The sensor described in claim 13, further comprising a filter and a frame capturing camera for detecting optical signatures indicative of a status of the chemical functionalities and optical signatures indicative of the encoding of the beads.

17. A method for constructing and using an analytic chemistry sensor, comprising:

forming wells at terminal ends of optical fibers within a bundle;

distributing beads carrying chemical functionalities within the wells; and

monitoring a status of the chemical functionalities from a proximal end of the bundle.

18. The method described in claim 17, wherein forming the wells comprises anisotropically etching of cores of the optical fibers with respect to cladding.

19. The method described in claim 17, further comprising forming a population of beads in the wells from separate subpopulations, each subpopulation carrying a different chemical functionality and an optically interrogatable code descriptive of the chemical functionality.

20. The method described in claim 19, further comprising randomly distributing the subpopulations within the wells.

21. The method described in claim 19, further comprising serially adding the subpopulations to the wells.

22. A composition comprising a plurality of optical fibers in an optical fiber array and a population of microspheres, wherein said optical fibers have wells at a first terminal end of said fibers and a plurality of said wells contain at least one microsphere.

23. A composition comprising:

a) a substrate;

b) a population of microspheres comprising separate subpopulations, each subpopulation comprising;

i) a chemical functionality for testing for interaction with a target analyte; and

ii) an encoding optical signature that can be used to identify said chemical functionality;

wherein said microspheres are distributed on said substrate.

24. A composition according to claim 23 wherein said substrate is an optical fiber array comprising a plurality of individual fibers and said microspheres are located within wells at a first terminal end of said fibers.

25. A composition according to claim 23 wherein said encoding optical signature comprises at least one chromophore.

26. A composition according to claim 23 wherein said encoding optical signature comprises at least one fluorescent dye.

27. A composition according to claim 26 wherein said fluorescent dye is entrapped within said microspheres.

28. A composition according to claim 26 wherein said fluorescent dye is attached to said microspheres.

29. A composition according to claim 26 wherein said encoding optical signature comprises a ratio of at least two or more fluorescent dyes.

30. A composition according to claim 26 wherein at least a first subpopulation of microspheres is a different size than a second subpopulation of microspheres.

31. A composition according to claim 24 wherein the individual fibers of said array are of uniform size.

32. A composition according to claim 24 wherein the individual fibers of said array are of a plurality of sizes.

33. A composition according to claim 23 wherein said chemical functionality is a nucleic acid.

34. A composition according to claim 23 wherein said chemical functionality is an antibody.

35. A composition according to claim 23 wherein said chemical functionality is an enzyme.

36. A composition according to claim 23 wherein said chemical functionality is selected from the group consisting of fluorophores, chromophores, phosphors, pH indicators, cation indicators, anion indicators, metal ion indicators, ion salt indicators, oxygen indicators and carbon dioxide indicators.

37. A composition according to claim 23 further comprising at least one target analyte interacting with at least one chemical functionality.

38. A composition according to claim 37 wherein said target analyte comprises at least one fluorophore.

39. A method of determining the presence of a target analyte in a sample comprising:

a) contacting said sample with a composition comprising;

i) a substrate;

ii) a population of microspheres comprising separate subpopulations, each subpopulation comprising;

1) a chemical functionality for testing for interaction with a target analyte; and

2) an encoding optical signature that can be used to identify said chemical functionality;

wherein said microspheres are distributed on said substrate; and

b) determining the presence or absence of the target analyte.

40. A method according to claim 39 wherein said substrate is an optical fiber array comprising a plurality of individual fibers and said microspheres are located within wells at a first terminal end of said fibers.

41. A method according to claim 39 further comprising identifying the location of each subpopulation on said substrate.

42. A method according to claim 39 wherein said encoding optical signature comprises at least one chromophore.

43. A method according to claim 39 wherein said encoding optical signature comprises at least one fluorescent dye.

45. A method according to claim 39 wherein said encoding optical signature comprises a ratio of at least two or more fluorescent dyes.

46. A method according to claim 39 wherein at least a first subpopulation of microspheres is a different size than a second subpopulation of microspheres.

47. A method according to claim 40 wherein the individual fibers of said array are of uniform size.

48. A method according to claim 40 wherein the individual fibers of said array are a plurality of sizes.

49. A method according to claim 39 wherein said target analyte is a nucleic acid.

50. A method according to claim 39 wherein said chemical functionality is a nucleic acid.

51. A method according to claim 39 wherein said chemical functionality is an enzyme.

52. A method according to claim 39 wherein said chemical functionality is an antibody.

53. A method according to claim 39 wherein said chemical functionality is selected from the group consisting of fluorophores, chromophores, phosphors, pH indicators, cation indicators, anion indicators, metal ion indicators, ion salt indicators, oxygen indicators and carbon dioxide indicators.

44. A method according to 43 wherein said fluorescent dye is entrapped within said microspheres.

54. A method of making a composition comprising:

a) forming wells at a terminal end of an optical fiber array; and

b) distributing microspheres within said wells, wherein said microspheres comprise separate subpopulations, each subpopulation comprising;

i) a chemical functionality for testing for interaction with a target analyte; and

ii) an encoding optical signature that can be used to identify said chemical functionality.

55. A method according to claim 54 wherein said forming comprises anisotropically etching the cores of the individual fibers of said array.

56. A method according to claim 55 wherein said distributing comprises serially adding said subpopulations to said wells.

57. A sensor comprising:

a) an array of optical fibers;

b) a population of microspheres comprising separate subpopulations, each subpopulation comprising;

i) a chemical functionality for testing for interaction with a target analyte; and

ii) an encoding optical signature that can be used to identify said chemical functionality;

wherein said microspheres are distributed on a first terminal end of said array; and

c) a light source.

58. A sensor according to claim 57 further comprising a light detector.