Intrinsic Raman spectroscopy

• US 9,103,793 B2
• Filed: 07/24/2006
• Issued: 08/11/2015
• Est. Priority Date: 07/22/2005
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Bechtel, Kate, Shih, Wei-Chuan, Feld, Michael S.
• Primary Examiner(s): Winakur, Eric
• Assistant Examiner(s): Fardanesh, Marjan
• Application Number:
  US11/492,214
• Publication Number:
  US 20070049809A1
• Time in Patent Office: 3,305 Days
• Field of Search: 600309-344
• US Class Current: 1/1
• 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 a blood analyte comprising:

a first light source that emits Raman excitation light;

a second light source;

a probe having a fiber optic light delivery and collection system for coupling the first light source and the second light source onto a region of material having an endogenous blood analyte, the system collecting Raman light and reflected light returning from the region of material;

a detector optically coupled to a proximal end of the probe that detects the collected Raman light and reflected light and generates Raman data and reflected light data; and

a processing system connected to the detector such that the processing system receives the Raman data and the reflected light data, the processing system processing the Raman data, reflected light data and a reference Raman spectrum of one or more blood analytes to provide spectral data indicating a concentration of the endogenous blood analyte in the region of material.

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

3. 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.

4. The system of claim 1 wherein the probe is coupled to a spectrograph.

5. The system of claim 1 wherein the processing system determines a ratio of Raman data and diffuse reflectance data to provide corrected spectral data.

6. The system of claim 1 wherein the second light source emits broadband light that is coupled to the optical delivery system.

7. The system of claim 1 wherein the first light source comprises an infrared laser.

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

9. The system of claim 1 wherein the fiber optic probe is coupled to a fiber optic coupler.

10. The system of claim 9 wherein system comprises a first fiber optic cable optically coupled to the first light source and a second fiber optic cable optically coupled to the second light source, a combiner optically coupling the first fiber optic cable and the second fiber optic cable to the probe fiber optic cable.

11. 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 first light source.

12. The system of claim 11 wherein the Raman excitation wavelength is in a range of 750 nm to 950 nm.

13. The system of claim 11 wherein the detector measures a Raman spectrum in response to the Raman excitation wavelength.

14. The system of claim 11 further comprising a processor that processes collected Raman data and collected reflected light data generated by the detector.

15. The system of claim 14 further comprising the processor is adapted to condition the Raman data with the reflected light data.

16. The system of claim 15 wherein the processor determines an area of a reflected light spectrum about a Raman excitation wavelength.

17. The system of claim 16 wherein the processor conditions the Raman data with said area.

18. The system of claim 17 wherein the processor divides a Raman spectrum with said area.

19. The system of claim 14 wherein the processor processes the Raman data to correct for measurement volume variations in a plurality of Raman data measurements.

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

21. The system of claim 20 further comprising the processor is adapted to define the transformation as a function including a spectral constraint.

22. The system of claim 21 wherein the spectral constraint comprises a spectrum of the analyte.

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

24. The system of claim 21 wherein the spectral constraint comprises a plurality of spectra of different analytes.

25. The system of claim 21 wherein the processor determines a minimized function to define the transformation.

26. The system of claim 20, wherein the processor 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 1 further comprising the probe has a light delivery fiber and a plurality of light collection optical fibers.

30. The system of claim 29 wherein the probe collects light returning from a region of skin of a subject.

31. The system of claim 30 further comprising a reflector that couples the returning light into a plurality of collection fibers.

32. The system of claim 31 wherein the probe couples the returning light to a spectrograph, the spectrograph coupling dispersed light to the detector.

33. The system of claim 29 wherein the probe has a distal filter.

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 first light source.

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

37. The system of claim 1 wherein the includes a light path with a reflector.

38. The system of claim 1 wherein the second light source comprises 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. A method of measuring a blood analyte comprising:

illuminating a material with light from a first light source and a second light source;

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

processing the detected Raman spectrum and the reflectance spectrum to provide a processed spectrum to measure an endogenous blood analyte within the material, the processing step including calculating a regularized spectrum using a reference Raman spectrum of one or more blood analytes.

41. The method of claim 40 further comprising determining a concentration of an analyte with the processed spectrum.

42. The method of claim 40 further comprising illuminating a sample with a laser excitation wavelength and detecting the reflected light spectrum and the Raman spectrum in response.

43. The method of claim 40 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.

44. The method of claim 40 further comprising storing a plurality of reference spectra in a memory, each reference spectrum corresponding to a separate blood analyte.

45. The method of claim 44 wherein the analytes comprise glucose, creatinine and urea.

46. The method of claim 40 further comprising delivering and a collecting light using a fiber optic probe.

47. The method of claim 46 further comprising collecting Raman light with a first plurality of collection fibers and collecting reflected light with a second plurality of collection fibers.

48. A system for measurement of a blood analyte comprising:

a first light source that emits a Raman excitation light;

a second light source;

an optical delivery system for coupling the first light source and the second light source through skin of a subject onto a region of material having an endogenous blood analyte;

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

a detector that detects the collected Raman and reflected light to generate Raman data and reflected light data; and

a processing system connected to the detector such that the processing system processes the Raman data, the reflected light data and a reference Raman spectrum of one or more blood analytes to measure the endogenous blood analyte.

49. The system of claim 48 wherein the processing system processes the Raman data and reflected light data to provide spectral data indicating a concentration of analyte in the region of material.

50. The system of claim 49 wherein the processing system determines a ratio of Raman data and diffuse reflectance data to provide corrected spectral data.

51. The system of claim 48 wherein the detector detects a diffuse reflectance spectrum and the processing system determines a sampling volume within a subject.

52. The system of claim 48 wherein the first light source comprises a laser that emits at a wavelength in a range of 750 nm to 1200 nm.

53. The system of claim 48 wherein the optical collection system comprises a fiber optic coupler and a spectrograph.

54. The system of claim 48 wherein the first 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.

55. The system of claim 54 wherein the detector detects the reflected light emission over a range of wavelengths of the narrowband light signal.

56. The system of claim 48 wherein the first light source comprises a laser.

57. The system of claim 48 wherein the first light source emits in a range of 750 nm to 1200 nm.

58. The system of claim 48 wherein the optical delivery system comprises a fiber optic delivery system.

59. The system of claim 48 wherein the detector measures a reflectance spectrum including light reflected by the material at a Raman excitation wavelength that is emitted by the first light source.

60. The system of claim 59 wherein the Raman excitation wavelength is in a range of 750 nm to 950 nm.

61. The system of claim 48 wherein the processing system processes collected Raman data and collected reflected light data generated by the detector to determine a glucose concentration.

62. The system of claim 61 wherein the processing system determines an area of a reflected light spectrum about a Raman excitation wavelength.

63. The system of claim 61 wherein the processing system processes the Raman data to correct for measurement volume variations in a plurality of Raman data measurements.

64. The system of claim 48 wherein the processing system processes the Raman data with the area of a reflected light spectrum.

65. The system of claim 64 wherein the processing system divides a Raman spectrum with said area.

66. The system of claim 48 wherein the processing system applies a transformation to a detected spectrum to determine an analyte concentration.

67. The system of claim 66 wherein the processing system applies the transformation as a function including a spectral constraint.

68. The system of claim 67 wherein the spectral constraint comprises a spectrum of the analyte.

69. The system of claim 68 wherein the analyte spectrum comprises a spectrum of glucose.

70. The system of claim 48 wherein the collected reflected light has a spectrum in a range of 750 nm to 950 nm.