Interferometric detection system and method

• US 7,835,013 B2
• Filed: 05/16/2008
• Issued: 11/16/2010
• Est. Priority Date: 05/18/2007
• Status: Expired due to Fees

• Current Assignee: Vanderbilt University
• Original Assignee: Vanderbilt University
• Inventors: Jones, Richard D., Bornhop, Darryl J.
• Primary Examiner(s): Toatley; Gregory J
• Assistant Examiner(s): Richey; Scott M
• Application Number:
  US12/122,175
• Publication Number:
  US 20090103091A1
• Time in Patent Office: 914 Days
• Field of Search: 356/517, 356/518, 356/520, 356/450
• US Class Current: 356/517
• CPC Class Codes: G01N 2021/4709 Backscatter
• CPC Class Codes: G01N 21/45 using interferometric methods; using Schlieren methods
• CPC Class Codes: G01N 2201/06113 Coherent sources; lasers

Abstract

Disclosed are improved optical detection systems and methods comprising interferometric detection systems, methods for determining a characteristic property of a fluid, methods for calculating a shift between at least two signals, computer program products encoded in a computer readable medium, and computational systems. Also disclosed are label-free, free-solution, and/or real-time measurements of characteristic properties and/or chemical events using the disclosed techniques. Also disclosed are various biosensor applications of the disclosed techniques. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Claims

1. An interferometric detection system comprising:

(a) a substrate;

(b) a channel formed in the substrate for reception of a fluid sample to be analyzed;

(c) a coherent light source for generating a coherent light beam, the light source being positioned to direct the light beam onto the substrate such that the light beam is incident on the channel to thereby generate backscattered light comprising interference fringe patterns;

(d) a photodetector for receiving the backscattered light and generating one or more intensity signals that vary as a function of positional shifts in the interference fringe patterns; and

(e) at least one signal analyzer for receiving the intensity signals and generating at least one of a signal A and a signal B, and determining therefrom a characteristic property of the fluid sample in the channel,

wherein the signal analyzer further comprises a processor programmed to determine a characteristic property of the fluid sample in the channel by performing a method comprising the steps of;

(i) determining a value q as a function of the sum of one or more overlapping products of signal A and signal B;

(ii) determining a value p as a function of the sum of one or more weighted overlapping products of signal A and signal B; and

(iii) calculating the shift between signal A and signal B as a function of p divided by q.

2. The system of claim 1, wherein signal A comprises n elements, signal B comprises m elements, and wherein determining a value q as a function of the sum of one or more overlapping products of signal A and signal B comprises:

(a) calculating a value k as a function of (n+m−

1); and

(b) determining a value q as a function of the sum of i overlapping products of signal A and signal B, wherein i comprises a set of values from 1 to k.

3. The system of claim 1, wherein signal A comprises n elements, signal B comprises m elements, and wherein determining a value p as a function of the sum of one or more weighted overlapping products of signal A and signal B comprises:

(a) calculating a value k as a function of (n+m−

1); and

(b) determining a value p as a function of the sum of i weighted overlapping products of signal A and signal B, wherein i comprises a set of values from 1 to k.

4. The system of claim 2, wherein the method further comprises determining a value p as a function of the sum of i weighted overlapping products of signal A and signal B.

5. The system of claim 2, wherein the weight for one or more overlapping products is taken from the set of values from 1 to a value c, wherein c is a function of n.

6. The system of claim 2, wherein determining a value p further comprises determining the weight as a function of (j−

c), wherein j comprises a set of values from 1 to k, and wherein c is a function of n.

7. The system of claim 1, wherein determining a value q as a function of the sum of one or more overlapping products of signal A and signal B comprises:

(a) computing an overlapping product of signal A and signal B, and assigning values to elements of a list R based on the overlapping product; and

(b) summing a set of elements from R to produce the value q.

8. The system of claim 7, wherein determining a value p as a function of the sum of one or more weighted overlapping products of signal A and signal B comprises:

(a) multiplying a set of elements from R by an odd function to create the one or more weighted overlapping products; and

(b) summing one or more products from the multiplying step to produce the value p.

9. The system of claim 1, wherein determining a value p as a function of the sum of one or more weighted overlapping products of signal A and signal B comprises:

(a) computing an overlapping product of signal A and signal B, and assigning values to elements of a list R based on the overlapping product;

(b) multiplying a set of elements from R by an odd function to create the one or more weighted overlapping products; and

(c) summing one or more products from the multiplying step to produce the value p.

10. The system of claim 7, wherein signal A comprises n elements and signal B comprises m elements, and wherein the computing step comprises:

(a) calculating a value k as a function of (n+m−

1);

(b) creating a list R comprising elements R1 through Rk; and

(c) assigning Ri a value based on the ith overlapping product of signal A and signal B, wherein i comprises a set of values from 1 to k.

11. The system of claim 8, wherein signal A comprises n elements and signal B comprises m elements, and wherein the multiplying step comprises multiplying Rj by (j−

c), wherein j comprises a set of values from 1 to a value k, wherein k is a function of (n+m−

1), and wherein c is a function of n.

12. The system of claim 1, wherein determining a value q as a function of the sum of one or more overlapping products of signal A and signal B comprises:

(a) assigning values to elements of a list R based on a Fourier transform of signal A and a Fourier transform of signal B; and

(b) summing a set of elements from R to produce the value q.

13. The system of claim 12, wherein determining a value p as a function of the sum of one or more weighted overlapping products of signal A and signal B comprises:

(a) multiplying a set of elements from R by an odd function to create the one or more weighted overlapping products; and

(b) summing one or more products from the multiplying step to produce the value p.

14. The system of claim 1, wherein determining a value p as a function of the sum of one or more weighted overlapping products of signal A and signal B comprises:

(a) assigning values to elements of a list R based on a Fourier transform of signal A and a Fourier transform of signal B;

(b) multiplying a set of elements from R by an odd function to create the one or more weighted overlapping products; and

(c) summing one or more products from the multiplying step to produce the value p.

15. The system of claim 12, wherein signal A comprises n elements and signal B comprises m elements, and wherein the assigning step comprises:

(a) calculating a value k as a function of (n+m−

1);

(b) creating a list R comprising elements R1 through Rk; and

(c) assigning Ri a value based on a Fourier transform of signal A and a Fourier transform of signal B, wherein i comprises a set of values from 1 to k.

16. The system of claim 13, wherein signal A comprises n elements and signal B comprises m elements, and wherein the multiplying step comprises multiplying Rj by (j−

c), wherein j comprises a set of values from 1 to a value k, wherein k is a function of (n+m−

1), and wherein c is a function of n.

17. The system of claim 1, wherein the substrate further comprises a reference channel.

18. The system of claim 1, wherein the fluid sample comprises at least one of a liquid or a gas.

19. The system of claim 1, wherein the substrate and channel together comprise a capillary tube.

20. The system of claim 1, wherein the channel comprises a microfluidic channel.

21. The system of claim 20, wherein the microfluidic device comprises a silica substrate and an etched channel formed in the substrate for reception of a fluid sample, the channel having a cross sectional shape.

22. The system of claim 21, wherein the cross sectional shape is substantially circular.

23. The system of claim 21, wherein the cross sectional shape is generally semi-circular.

24. The system of claim 1, wherein the coherent light beam is a laser.

25. The system of claim 1, further comprising a chromatographic separator or an electrophoretic separator in fluid connection with the channel.

26. The system of claim 1, further comprising a display, wherein the characteristic property of the sample in the channel as determined by the shift between signal A and signal B is displayed.

27. A method for determining a characteristic property of a sample comprising the steps of:

(a) providing a substrate having a channel formed therein for reception of a fluid sample to be analyzed;

(b) introducing a fluid sample to be analyzed into the channel;

(c) directing a coherent light beam onto the substrate such that the light beam is incident on the channel to generate backscattered light comprising interference fringe patterns;

(d) detecting positional shifts in the interference fringe patterns and generating at least a signal A and a signal B from the detected positional shifts; and

(e) determining the characteristic property of the sample from the positional shifts in the interference patterns by performing a method comprising the steps of;

(i) determining a value q as a function of the sum of one or more overlapping products of signal A and signal B;

(ii) determining a value p as a function of the sum of one or more weighted overlapping products of signal A and signal B; and

(iii) calculating the shift between signal A and signal B as a function of p divided by q.

28. The method of claim 27, wherein signal A comprises n elements, signal B comprises m elements, and wherein determining a value q as a function of the sum of one or more overlapping products of signal A and signal B comprises:

(a) calculating a value k as a function of (n+m−

1); and

(b) determining a value q as a function of the sum of i overlapping products of signal A and signal B, wherein i comprises a set of values from 1 to k.

29. The method of claim 27, wherein signal A comprises n elements, signal B comprises m elements, and wherein determining a value p as a function of the sum of one or more weighted overlapping products of signal A and signal B comprises:

(a) calculating a value k as a function of (n+m−

1); and

(b) determining a value p as a function of the sum of i weighted overlapping products of signal A and signal B, wherein i comprises a set of values from 1 to k.

30. The method of claim 28, wherein the method further comprises determining a value p as a function of the sum of i weighted overlapping products of signal A and signal B.

31. The method of claim 28, wherein the weight for one or more overlapping products is taken from the set of values from 1 to a value c, wherein c is a function of n.

32. The method of claim 28, wherein determining a value p further comprises determining the weight as a function of (j−

c), wherein j comprises a set of values from 1 to k, and wherein c is a function of n.

33. The method of claim 27, wherein determining a value q as a function of the sum of one or more overlapping products of signal A and signal B comprises:

(a) computing an overlapping product of signal A and signal B, and assigning values to elements of a list R based on the overlapping product; and

(b) summing a set of elements from R to produce the value q.

34. The method of claim 33, wherein determining a value p as a function of the sum of one or more weighted overlapping products of signal A and signal B comprises:

(a) multiplying a set of elements from R by an odd function to create the one or more weighted overlapping products; and

(b) summing one or more products from the multiplying step to produce the value p.

35. The method of claim 27, wherein determining a value p as a function of the sum of one or more weighted overlapping products of signal A and signal B comprises:

(a) computing an overlapping product of signal A and signal B, and assigning values to elements of a list R based on the overlapping product;

(b) multiplying a set of elements from R by an odd function to create the one or more weighted overlapping products; and

(c) summing one or more products from the multiplying step to produce the value p.

36. The method of claim 33, wherein signal A comprises n elements and signal B comprises m elements, and wherein the computing step comprises:

(a) calculating a value k as a function of (n+m−

1);

(b) creating a list R comprising elements R1 through Rk; and

(c) assigning Ri a value based on the ith overlapping product of signal A and signal B, wherein i comprises a set of values from 1 to k.

37. The method of claim 34, wherein signal A comprises n elements and signal B comprises m elements, and wherein the multiplying step comprises multiplying Rj by (j−

c), wherein j comprises a set of values from 1 to a value k, wherein k is a function of (n+m−

1), and wherein c is a function of n.

38. The method of claim 27, wherein determining a value q as a function of the sum of one or more overlapping products of signal A and signal B comprises:

(a) assigning values to elements of a list R based on a Fourier transform of signal A and a Fourier transform of signal B; and

(b) summing a set of elements from R to produce the value q.

39. The method of claim 38, wherein determining a value p as a function of the sum of one or more weighted overlapping products of signal A and signal B comprises:

(a) multiplying a set of elements from R by an odd function to create the one or more weighted overlapping products; and

(b) summing one or more products from the multiplying step to produce the value p.

40. The method of claim 27, wherein determining a value p as a function of the sum of one or more weighted overlapping products of signal A and signal B comprises:

(a) assigning values to elements of a list R based on a Fourier transform of signal A and a Fourier transform of signal B;

(b) multiplying a set of elements from R by an odd function to create the one or more weighted overlapping products; and

(c) summing one or more products from the multiplying step to produce the value p.

41. The method of claim 38, wherein signal A comprises n elements and signal B comprises m elements, and wherein the assigning step comprises:

(a) calculating a value k as a function of (n+m−

1);

(b) creating a list R comprising elements R1 through Rk; and

(c) assigning Ri a value based on a Fourier transform of signal A and a Fourier transform of signal B, wherein i comprises a set of values from 1 to k.

42. The method of claim 39, wherein signal A comprises n elements and signal B comprises m elements, and wherein the multiplying step comprises multiplying Rj by (j−

c), wherein j comprises a set of values from 1 to a value k, wherein k is a function of (n+m−

1), and wherein c is a function of n.

43. The method of claim 27, wherein the substrate further comprises a reference channel.

44. The method of claim 27, wherein the fluid sample comprises at least one of a liquid or a gas.

45. The method of claim 27, wherein the positional shifts correspond to a chemical event occurring in the sample.

46. The method of claim 45, wherein the chemical event is a binding event between one or more of antibody-antigen, protein-protein, small molecule-small molecule;

small molecule-protein, drug-receptor;

antibody-cell;

protein-cell;

oligonucleotide-cell;

carbohydrate-cell;

cell-cell;

enzyme-substrate;

protein-DNA;

protein-aptamer;

DNA-DNA;

RNA-RNA;

DNA-RNA;

protein-RNA;

small molecule-nucleic acid;

biomolecule-molecular imprint;

biomolecule-protein mimetic;

biomolecule-antibody derivatives;

lectin-carbohydrate; and

biomolecule-carbohydrate.

47. The method of claim 27, wherein the substrate and channel together comprise a capillary tube.

48. The method of claim 27, wherein the channel comprises a microfluidic channel.

49. The method of claim 48, wherein the microfluidic device comprises a silica substrate and an etched channel formed in the substrate for reception of a fluid sample, the channel having a cross sectional shape.

50. The method of claim 49, wherein the cross sectional shape is substantially circular.

51. The method of claim 49, wherein the cross sectional shape is generally semi-circular.

52. The method of claim 27, wherein the coherent light beam is produced by a laser.

53. The method of claim 27, further comprising the step of performing a chromatographic separation on the sample prior to the determining the characteristic property step.

54. The method of claim 32, further comprising the step of performing an electrophoretic separation on the sample prior to the determining the characteristic property step.

55. The method of claim 27, further comprising the step of displaying the characteristic property of the sample in the channel as determined by the shift between signal A and signal B.

56. The method of claim 27, wherein the substrate comprises at least a second channel formed therein for reception of a second fluid sample to be analyzed, further comprising the steps of:

(f) introducing the second fluid sample to be analyzed into the second channel;

(g) directing a coherent light beam onto the substrate such that the light beam is incident on the second channel to generate backscattered light comprising interference fringe patterns;

(h) detecting positional shifts in the interference fringe patterns and generating at least a signal A and a signal B from the detected positional shifts; and

(i) determining the characteristic property of the second sample from the positional shifts in the interference fringe patterns by performing a method comprising the steps of;

(i) determining a value q as a function of the sum of one or more overlapping products of signal A and signal B;

(ii) determining a value p as a function of the sum of one or more weighted overlapping products of signal A and signal B; and

(iii) calculating the shift between signal A and signal B as a function of p divided by q.

57. The method of claim 56, wherein the fluid sample is analyzed in the channel and the second fluid sample is analyzed in the second fluid channel simultaneously.

58. The method of claim 27, wherein the step of introducing the fluid sample to be analyzed into the channel comprises flowing the fluid sample through the channel and sequentially introducing at least a second fluid sample into the channel.