Intrinsic Raman spectroscopy

• US 20070049809A1
• Filed: 07/24/2006
• Published: 03/01/2007
• Est. Priority Date: 07/22/2005
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Shih, Wei-Chuan, Feld, Michael, Bechtel, Kate
• Granted Patent: US 9,103,793 B2
• Time in Patent Office: Days
• US Class Current: 600/316
• CPC Class Codes: A61B 2560/0223 of calibration, e.g. protocols for calibrating sensors
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/14546 for measuring analytes not otherwise provided for, e.g. ions, cytochromes
• CPC Class Codes: A61B 5/1455 using optical sensors, e.g. spectral photometrical oximeters
• CPC Class Codes: A61B 5/1495 Calibrating or testing of in-vivo probes
• CPC Class Codes: G01N 21/65 Raman scattering

Abstract

The present invention relates to systems and methods for the measurement of analytes such as glucose. Raman and reflectance spectroscopy are used to measure a volume, of material such as a blood sample or tissue within a subject and determine a concentration of a blood analyte based thereon. The present invention further relates to a calibration method, constrained regularization (CR), and demonstrates its use for analyzing spectra including, for example, the measurement glucose concentrations using transcutaneous Raman spectroscopy.

Claims

1. A system for measurement of blood analyte comprising:

a light source that emits a Raman excitation light;

an optical delivery system for coupling the light source and onto a region of material having an analyte;

an optical collection system that collects Raman and reflected light returning from the region; and

a detector that detects the collected Raman and reflected light.

2. The system of claim 1 further comprising a processing system connected to the detector such that the processing system receives Raman data and reflected light data, the system processing the Raman data and reflected light data to provide spectral data indicating a concentration of analyte in the region of material.

3. The system of claim 1 wherein the detector detects a diffuse reflectance spectrum and the processor determines a sampling volume within the subject.

4. The system of claim 1 wherein the first light source comprises a laser that emits at a wavelength in a range of 750 nm to 1200 nm.

5. The system of claim 1 wherein the optical collection system comprises a fiber optic coupler and a spectrograph.

6. The system of claim 2 wherein the processing system determines a ratio of Raman data and diffuse reflectance data to provide corrected spectral data.

7. The system of claim 1 further comprising a second light source that emits broadband light that is coupled to the optical delivery system.

8. The system of claim 1 wherein the light source comprises a laser.

9. The system of claim 1 wherein the light source emits in a range of 750 nm to 1200 nm.

10. The system of claim 1 wherein the optical delivery system comprises a fiber optic delivery system.

11. The system of claim 10 wherein the fiber optic delivery system comprises a first fiber optic cable optically coupled to the light source and a second fiber optic cable optically coupled to a second light source, a combiner optically coupling the first fiber optic cable and the second fiber optic cable to a third fiber optic cable.

12. The system of claim 1 wherein the detector measures a reflectance spectrum including light reflected by the material at a Raman excitation wavelength that is emitted by the light source.

13. The system of claim 12 wherein the Raman excitation wavelength is in a range of 750 nm to 950 nm.

14. The system of claim 12 wherein the detector measures a Raman spectrum in response to the Raman excitation wavelength.

15. The system of claim 12 further comprising a processor that processes collected Raman data and collected reflected light data generated by the detector.

16. The system of claim 15 further comprising a software program that conditions the Raman data with the reflected light data.

17. The system of claim 16 wherein the software program determines an area of a reflected light spectrum about a Raman excitation wavelength.

18. The system of claim 17 wherein the software program conditions the Raman data with said area.

19. The system of claim 18 wherein the software program divides a Raman spectrum with said area.

20. The system of claim 15 wherein the processor processes the Raman data to correct for measurement volume variations in a plurality of Raman data measurements.

21. The system of claim 1 further comprising a processor connected to detector that applies a transformation to a detected spectrum to determine an analyte concentration.

22. The system of claim 21 further comprising a computer program that defines the transformation as a function including a spectral constraint.

23. The system of claim 22 wherein the spectral constraint comprises a spectrum of the analyte.

24. The system of claim 23 wherein the analyte spectrum comprises a spectrum of glucose.

25. The system of claim 22 wherein the spectral constraint comprises a plurality of spectra of different analytes.

26. The system of claim 21 further comprising a computer program that processes the detected Raman spectrum and a detected reflectance spectrum in combination with the transformation to provide a corrected spectrum.

27. The system of claim 26 wherein the transformation comprises a spectral constraint.

28. The system of claim 1 further comprising a calibration phantom.

29. The system of claim 22 wherein the computer program determines a minimized function to define the transformation.

30. The system of claim 1 further comprising a fiber optic probe having a light delivery fiber of the optical delivery system and a plurality of light collection optical fibers of the optical collection system.

31. The system of claim 30 wherein the optical collection system comprises a parabolic reflector that reflects light returning from a region of skin of a subject.

32. The system of claim 31 wherein the reflector couples the returning light into a fiber optic cable.

33. The system of claim 32 wherein the fiber optic coupler couples the returning light to a spectrograph, the spectrograph coupling dispersed light to the detector.

34. The system of claim 1 further comprising a second detector that monitors light source output.

35. The system of claim 1 further comprising a controller that actuates the light source.

36. The system of claim 35 wherein the controller actuates a shutter device.

37. The system of claim 1 wherein the light delivery system includes a light path through a reflector of the light collection system.

38. The system of claim 1 further comprising a white light source that is coupled to the material for a reflectance measurement.

39. The system of claim 1 further comprising a container that contains a sample of material removed from a body to be measured by the system.

40. The system of claim 30 wherein the probe has a distal filter.

41. A method for analyzing a spectrum comprising:

providing a spectrum to be analyzed; and

applying a transformation to the spectrum, the transformation including a spectral constraint.

42. The method of claim 41 further comprising providing a Raman spectrum to be analyzed.

43. The method of claim 42 further comprising providing a Raman spectrum of a blood glucose measurement of a subject.

44. The method of claim 43 wherein the spectral constraint comprises a spectrum of glucose.

45. The method of claim 41 wherein the step of applying a transformation comprises applying a regularized calibration vector including a spectrum of an analyte.

46. The method of claim 41 wherein the method comprises calibrating a spectrum.

47. The method of claim 45 wherein the step of applying the regularized calibration vector comprises determining a product of a measured spectrum and a regularized calibration vector.

48. The method of claim 45 further comprising determining the regularized calibration vector by summing a plurality of regularized components and a plurality of spectrally constrained components.

49. The method of claim 41 wherein the step of providing a spectrum comprises providing a measured Raman spectrum that is processed using a reflectance spectrum.

50. A method of measuring an analyte comprising directing light onto a material to be measured;

detecting a Raman spectrum and a reflectance spectrum from the material in response to the light; and

processing the Raman spectrum and the reflectance spectrum to provide a processed spectrum.

51. The method of claim 50 further comprising determining a concentration of an analyte with the processed spectrum.

52. The method of claim 50 further comprising illuminating a sample with a laser excitation wavelength and detecting the reflected light spectrum and the Raman spectrum in response.

53. The method of claim 50 further comprising illuminating a sample with a first narrowband light source to measure the Raman spectrum and a broadband light source to measure the reflectance spectrum.

54. A method of analyzing a spectrum to measure a blood analyte comprising:

processing a Raman spectrum of a material containing a blood analyte with a reflectance spectrum of the material to provide a processed spectrum.

55. The method of claim 54 further comprising calibrating the processed spectrum with constrained regularization.

56. The method of claim 55 further comprising determining an area of the reflectance spectrum and determining a ratio of the Raman spectrum and said area.

57. The method of claim 54 further comprising determining a concentration of the analyte in the material.

58. The method of claim 57 further -comprising determining a blood glucose concentration.

59. The method of claim 55 further comprising determining a regularization vector including a spectral constraint comprising a spectrum of. the analyte.

60. A system for measurement of an analyte comprising:

a light source that emits a Raman excitation light;

an optical delivery system for coupling the light source and onto a region of material having an analyte;

an optical collection system that collects Raman and reflected light returning from the region in response to the Raman excitation light; and

a detector that detects the collected Raman and reflected light.

61. The system of claim 60 further comprising a processing system connected to the detector such that the processing system receives Raman data and reflected light data, the system processing the Raman data and reflected light data to provide spectral data indicating a concentration of analyte in the region of material.

62. The system of claim 60 wherein the detector detects a diffuse reflectance spectrum and the processor determines a sampling volume within the subject.

63. The system of claim 60 wherein the first light source comprises a laser that emits at a wavelength in a range of 750 nm to 1200 nm.

64. The system of claim 60 wherein the optical collection system comprises a fiber optic coupler and a spectrograph.

65. The system of claim 61 wherein the processing system determines a ratio of Raman data and diffuse reflectance data to provide corrected spectral data.

66. The system of claim 60 wherein the light source emits a single narrowband light signal to induce a Raman light emission and a reflected light emission that are detected by the detector.

67. The system of claim 60 wherein the light source comprises a laser.

68. The system of claim 60 wherein the light source emits in a range of 750 nm to 1200 nm.

69. The system of claim 60 wherein the optical delivery system comprises a fiber optic delivery system.

70. The system of claim 66 wherein the detector detects the reflected light emission over a range of wavelengths of the narrowband light signal.

71. The system of claim 60 wherein the detector measures a reflectance spectrum including light reflected by the material at. a Raman excitation wavelength that is emitted by the light source.

72. The system of claim 71 wherein the Raman excitation wavelength is in a range of 750 nm to 950 nm.

73. The system of claim 60 further comprising a processor that processes collected Raman data and collected reflected light data generated by the detector.

74. The system of claim 60 further comprising a software program that processes the Raman data with the area of a reflected light spectrum.

75. The system of claim 60 wherein the software program determines an area of a reflected light spectrum about a Raman excitation wavelength.

76. The system of claim 74 wherein the software program divides a Raman spectrum with said area.

77. The system of claim 73 wherein the processor processes the Raman data to correct for measurement volume variations in a plurality of Raman data measurements.

78. The system of claim 60 further comprising a processor connected to detector that applies a transformation to a detected spectrum to determine an analyte concentration.

79. The system of claim 78 further comprising a computer program that defines the transformation as a function including a spectral constraint.

80. The system of claim 79 wherein the spectral constraint comprises a spectrum of the analyte.

81. The system of claim 80 wherein the analyte spectrum comprises a spectrum of glucose.

82. The system of claim 60 wherein the collected reflected light has a spectrum in a range of 750 nm to 950 nm.