Non-spectrophotometric measurement of analyte concentrations and optical properties of objects

• US 5,434,412 A
• Filed: 10/01/1993
• Issued: 07/18/1995
• Est. Priority Date: 07/15/1992
• Status: Expired due to Fees

• Current Assignee: Optix LP
• Original Assignee: Myron J. Block
• Inventors: Block, Myron J., Sodickson, Lester
• Primary Examiner(s): Dzierzynski, Paul M.
• Assistant Examiner(s): HANIG, RICHARD E
• Application Number:
  US08/130,257
• Time in Patent Office: 655 Days
• Field of Search: 250/343, 250/339.02, 250/339.11, 250/339.12, 250/341, 250/340, 356/405
• US Class Current: 250/343
• 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 5/6826 Finger
• CPC Class Codes: A61B 5/6838 Clamps or clips
• CPC Class Codes: G01N 2021/3137 with selection of wavelengths after the sample
• CPC Class Codes: G01N 21/31 Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry G01N21/72 takes precedence
• CPC Class Codes: G01N 21/359 using near infrared light
• CPC Class Codes: G01N 21/4795 spatially resolved investigating of object in scattering medium in vivo A61B

Abstract

Improvements in non-invasive detection methods for glucose and other constituents of interest in a sample have been developed. The apparatus and methods of the invention provide an analog of color perception of human vision, preferably in the near infrared region, replacing spectrophotometers and narrow band sources used in other non-invasive near infrared detection methods. A plurality of detector units are used, each covering a broad and overlapping region of the detected spectrum, paralleling color perception and colorimetry. The improvements are primarily concerned with improving the signal-to-background (or noise) ratio such that the data stream is improved. These improvements use congruent sampling, comparison of different data streams from different sample portions or filter sets, using an interrogation system with sufficient speed to allow testing of arterial blood, and using a filter with a spectral structure. In some circumstances, a neural net is used for analysis, allowing the system to learn. A novel method for background discrimination is also described.

Claims

1. In an apparatus for determining the concentration of a constituent of interest in a sample having:

a radiation source generating a spectrum of illuminating radiation for illuminating a portion of said sample;

a sample chamber for fixing said portion of said sample in a substantially fixed location relative to said radiation source;

detection means having a plurality of detectors adapted to generate an output responsive to radiation transmitted by emitted by or reflected from, said sample, each of said detectors having a spectral response in a portion of said spectrum of illuminating radiation emitted by said radiation source, each of said detectors having a separate peak spectral response and at least a partial overlap in spectral response characteristics with that of at least one other of said detectors; and

analysis means tier analyzing said outputs from the detectors to generate a signal indicative of the concentration of said constituent;

the improvement comprising;

said apparatus being constructed such that each of said detectors is located such that it congruently samples the radiation from said sample.

2. The apparatus of claim 1 wherein said illuminating radiation comprises infrared radiation in the 700-2500 nm range.

3. The apparatus of claim 1 wherein said analysis means generates an output which is an analog of a location in a colorimetric n-dimensional space, n being equal to, or less than, the number of detectors in said detection means.

4. The apparatus of claim 1 wherein said detector means further comprises a black/white luminosity detector which is responsive to and overlaps said spectral response of all of said plurality of detectors.

5. The apparatus of claim 1 wherein each of said detectors comprises a filter which transmits or reflects a portion of said spectrum of illuminating radiation, each of said filters having a separate peak transmittance or absorbance response different from the peak transmittance or reflectance responses of the other filters of said detection means and at least a partial overlap in transmittance or reflectance response with at least one other of said filters.

6. The apparatus of claim 1 wherein said analysis means comprises a neural network.

7. The apparatus of claim 1 wherein at least one of said plurality of detectors comprises a silicon photocell.

8. The apparatus of claim 1 wherein said sample comprises a portion of a human body.

9. The apparatus of claim 1 wherein said constituent of interest is selected from the group consisting of glucose, glucose indicating constituents, cholesterol, lipids, proteins, hemoglobin and its variants, drugs of abuse and drugs of abuse indicating constituents.

10. The apparatus of claim 1 comprising beam splitting means to allow said plurality of detectors to be arranged to achieve congruent sampling.

11. The apparatus of claim 1 comprising a fiber optic cable bundles containing a plurality of optical fibers to allow said plurality of detectors to be arranged to achieve congruent sampling.

12. In an apparatus for determining the concentration of a constituent of interest in a sample having:

a radiation source generating a spectrum of illuminating radiation for illuminating a portion of said sample;

a sample chamber for fixing said portion of said sample in a substantially fixed location relative to said radiation source;

detection means having a plurality of detectors adapted to generate an output responsive to radiation transmitted by emitted by, or reflected from said sample, each of said detectors having a spectral response in a portion of said spectrum of illuminating radiation emitted by said radiation source, each of said detectors having a separate peak spectral response and at least a partial overlap in spectral response characteristics with that of at least one other of said detectors; and

analysis means for analyzing the outputs from said detectors to generate a data signal indicative of the concentration of said constituent;

the improvement comprising;

having at least two detection means, a first detection means generating a first data stream formed of a composite of a data signal component indicative of said concentration of said constituent and a background component and a second detection means generating a second data stream formed of a composite of a data signal component indicative of said concentration of said constituent and a background component; and

said analysis means comprising means adapted for comparing said first data stream with said second data stream in order to generate an information signal indicative of the concentration of said constituent while rendering the interfering features of the background from said first and second data streams to be less distinct than the background is in either data stream individually.

13. The apparatus of claim 12 wherein each of said detectors comprises a filter which transmits or reflects a portion of said spectrum of illuminating radiation, each of said filters having a peak transmittance or reflectance response different from the peak transmittance or reflectance responses of the other filters of said detection means and at least a partial overlap in transmittance or absorbance response with at least one other filter, said first detection means having a first set of filters and said second detection means having a second set of filters, and said first and second sets of filters having differing transmittance or reflectance responses.

14. The apparatus of claim 12 wherein said illuminating radiation comprises infrared radiation in the 700-2500 nm range.

15. The apparatus of claim 12 wherein said analysis means generates an analog of a location in a colorimetric n-dimensional space from said first data stream, where n is equal to or less than, the number of detectors in each of said first detection means;

an analog of a location in a colorimetric m-dimensional space from said second data stream, where m is equal to or less than, the number of detectors in said second detection means; and

compares said locations to generate said data signal indicative of concentration.

16. The apparatus of claim 12 wherein at least one of said detection means further comprises a black/white luminosity detector which is responsive to and overlaps said spectral response of all of said plurality of detectors in said detection means.

17. The apparatus of claim 12 wherein said analysis means comprises a neural network.

18. The apparatus of claim 12 wherein at least one of said plurality of detectors comprises a silicon photocell.

19. The apparatus of claim 12 wherein said sample comprises a portion of a human body.

20. The apparatus of claim 12 wherein said constituent of interest is selected from the group consisting of glucose, glucose indicating constituents, cholesterol, lipids, proteins, hemoglobin and its variants, drugs of abuse and drugs of abuse indicating constituents.

21. The apparatus of claim 12 wherein said apparatus comprises at least two sample chambers, each of said sample chambers being arranged such that radiation passing there through falls on only one, but not both, of said first and second detection means.

22. In an apparatus for determining the concentration of a constituent of interest in a sample having:

a radiation source generating a spectrum of illuminating radiation for illuminating a portion of said sample;

at least one sample chamber for fixing said portion of said sample in a substantially fixed location relative to said radiation source;

detection means having a plurality of detectors adapted to generate an output, each of said detectors having a spectral response to a portion of said spectrum of illuminating radiation emitted by said radiation source, each of said detector having a separate peak spectral response and at least a partial overlap in spectral response characteristics with that of a least one other of said detectors; and

analysis means for analyzing the outputs from said detectors to generate a data signal component component indicative of the concentration of said constituent;

the improvement comprising;

having at least two detection means, a first detection means adapted to receive radiation transmitted or reflected from a first sample portion which is in a first sample chamber, said first detector means generating a first data stream formed of a composite of a data signal component indicative of said concentration of said constituent and a background component, and a second detection means adapted to receive radiation transmitted or reflected from a second sample portion which is in a second sample chamber, said second detection means generating a second data stream formed of a composite of a data signal component indicative of said concentration of said constituent and a background component; and

said analysis means comprising means adapted for comparing said first data stream with said second data stream in order to generate an information signal indicative of the concentration of said constituent while rendering the interfering features of the background from said first data stream and said second data stream to be less distinct than the background is in either data stream individually.

23. The apparatus of claim 22 wherein each of said detectors has a filter with a peak spectral response different from the peak spectral responses of the other filters of said detection means and at least a partial overlap in spectral response with at least one other filter, said first detection means having a first set of filters and said second detection means having a second set of filters, and said first and second sets of filters having differing spectral transmittance or reflectance responses.

24. The apparatus of claim 22 wherein said illuminating radiation comprises infrared radiation in the 700-2500 nm range.

25. The apparatus of claim 22 wherein said analysis means generates an analog of a location in a colorimetric n-dimensional space from said first data stream, where n is equal to or less than, the number of detectors in each of said first detection means;

an analog of a location in a colorimetric m-dimensional space from said second data stream, where m is equal to or less than, the number of detectors in said second detection means; and

compares said locations to generate said data signal component indicative of concentration.

26. The apparatus of claim 22 wherein at least one of said detection means further comprises a black/white luminosity detector which is responsive to and overlaps said spectral response of all of said plurality of detectors in said detection means.

27. The apparatus of claim 22 wherein said analysis means comprises a neural network.

28. The apparatus of claim 22 wherein at least one of said plurality of detectors comprises a silicon photocell.

29. The apparatus of claim 22 wherein said sample comprises a portion of a human body.

30. The apparatus of claim 22 wherein said constituent of interest is selected from the group consisting of glucose, glucose indicating constituents, cholesterol, lipids, proteins, hemoglobin and its variants, drugs of abuse and drugs of abuse indicating constituents.

31. In an apparatus for determining the concentration of a constituent in a sample having:

a radiation source generating a spectrum of illuminating radiation for illuminating a portion of said sample;

a sample chamber for fixing said portion of said sample in a substantially fixed location relative to said radiation source;

detection means having a plurality of detectors adapted to generate an output, each of said detectors having a filter which transmits or reflects a portion of the spectrum of illuminating radiation emitted by said radiation source, each of said filters having a separate peak transmittance or reflection response and at least a partial overlap in transmittance or reflectance characteristics with at least one other of said filters; and

analysis means for analyzing the outputs from the detectors to generate a signal indicative of the concentration of said constituent;

the improvement comprising;

having at least one of said filters in said detection means being selected from the group consisting of filters having spectral structure such that it has multiple absorbance bands in the portion of the spectrum over which it transmits or reflects radiation, and filters which have only a single narrow transmittance or reflectance range.

32. The apparatus of claim 31 wherein said illuminating radiation comprises infrared radiation in the 700-2500 nm range.

33. The apparatus of claim 31 wherein said analysis means generates an output which is an analog of a location in a colorimetric n-dimensional space, n being equal to, or less than, the number of detectors in said detection means.

34. The apparatus of claim 31 wherein said detector means further comprises a black/white luminosity detector which is responsive to and overlaps said spectral response of all of said plurality of detectors.

35. The apparatus of claim 31 wherein said analysis means comprises a neural network.

36. The apparatus of claim 31 wherein at least one of said plurality of detectors comprises a silicon photocell.

37. The apparatus of claim 31 wherein said sample comprises a portion of a human body.

38. The apparatus of claim 31 wherein said constituent of interest is selected from the group consisting of glucose, glucose indicating constituents, cholesterol, lipids, proteins, hemoglobin and its variants, drugs of abuse and drugs of abuse indicating constituents.

39. The apparatus of claim 31 wherein said spectral structure of said filter is in the form of a sinusoidal transmittance or reflectance structure.

40. In an apparatus for determining the concentration of a constituent in a sample having:

a radiation source generating a spectrum of illuminating radiation for illuminating a portion of said sample;

a sample chamber for fixing said portion of said sample in a substantially fixed location relative to said radiation source;

detection means having a plurality of detectors adapted to generate an output, each of said detectors having a spectral response in a portion of the spectrum of illuminating radiation emitted by said radiation source, each of said detectors having a separate peak spectral response and at least a partial overlap in spectral response characteristics with at least one other of said detectors; and

analysis means for analyzing the outputs from the detectors to generate a data signal component indicative of the concentration of said constituent;

the improvement comprising;

providing interrogation means which collects the outputs from said detectors in sufficiently rapid manner to observe a distinct arterial pulse wave form so to allow differentiation of constituents of interest in arterial blood, as opposed to venous or tissue blood, in said sample.

41. The apparatus of claim 40 wherein each of said detectors comprises a filter which transmits or reflects a portion of said spectrum of illuminating radiation, each of said filters having a separate peak transmittance or absorbance response different from the peak transmittance or reflectance responses of the other filters of said detection means and at least a partial overlap in transmittance or reflectance response with at least one other of said filters.

42. The apparatus of claim 40 wherein said illuminating radiation comprises infrared radiation in the 700-2500 range.

43. The apparatus of claim 40 wherein said analysis means generates an output which is an analog of a location in a colorimetric n-dimensional space, where n is equal to, or less than, the number of detectors in said detection means.

44. The apparatus of claim 40 wherein said detection means further comprises a black/white luminosity detector which is responsive to and overlaps said spectral response of all of said plurality of detectors.

45. The apparatus of claim 40 wherein said analysis means comprises a neural network.

46. The apparatus of claim 40 wherein each of said plurality of detectors comprise silicon photocells.

47. The apparatus of claim 40 wherein said sample comprises a portion of a human body.

48. The apparatus of claim 40 wherein said constituent of interest is selected from the group consisting of glucose, glucose indicating constituents, cholesterol, lipids, proteins, hemoglobin and its variants, drugs of abuse and drugs of abuse indicating constituents.

49. The apparatus of claim 40 whereby said apparatus comprises a plurality of sample chambers, each sample chamber being adapted to hold a separate portion of mammalian tissue.

50. The apparatus of claim 49 wherein each of said sample chambers has a detection means associated therewith, each of said individual detection means having its own set of filters associated therewith.

51. A method for determining the concentration of a constituent of interest in a sample comprising the steps of:

fixing a portion of said sample of interest in a position such that it can be illuminated with a spectrum of radiation from a radiation source;

illuminating said portion of said sample of interest with said spectrum of radiation from said radiation source;

detecting radiation transmitted or reflected from said sample, said detection being carried out by detection means containing a plurality of individual detectors, each of said detectors having a peak spectral response distinct from the peak spectral response any other of said detectors, said detectors each having overlap in spectral response with at least one of said other detectors, each of said detectors being located relative to said fixed portion of said sample such that each of said detectors provides congruent sampling with the others of said detectors;

generating a data stream corresponding to said detected radiation from each of said detectors; and

analyzing said data streams to obtain a measure of concentration.

52. The method of claim 51 wherein each of said detectors further comprise an associated filter, each of said associated filters having a peak transmittance or reflectance distinct from the peak transmittance or reflectance of any of the other of said filters, each of said filters having an overlap in spectral response with at least one other of said filters.

53. The method of claim 51 wherein said spectrum of illuminating radiation comprises infrared radiation in the 700-2500 nm range.

54. The method of claim 51 wherein said analysis step comprises forming an analog of a specific position in an n-dimensional colorimetric space from said data stream, n being equal to, or less than, the number of detectors in said detection means.

55. The method of claim 51 wherein said analysis step is carried out by a neural network.

56. The method of claim 51 wherein said neural network is calibrated and trained to process said data streams to achieve an analog of color constancy in vision.

57. The method of claim 51 wherein said constituent of interest is selected from the group consisting of glucose, glucose indicating constituents, cholesterol, lipids, proteins, hemoglobin and its variants, drugs of abuse, and drugs of abuse indicating constituents.

58. The method of claim 51 wherein said sample comprises a portion of a human body.

59. The method of claim 51 comprising beam splitting means to allow said plurality of detectors to be arranged to achieve congruent sampling.

60. The method of claim 51 comprising a fiber optic cable bundles containing a plurality of optical fibers to allow said plurality of detectors to be arranged to achieve congruent sampling.

61. A method for determining the concentration of a constituent of interest in a sample comprising the steps of:

fixing a portion of said sample of interest in a position such that it can be illuminated with a spectrum of radiation from a radiation source;

illuminating said portion of said sample of interest with said spectrum of radiation from said radiation source;

detecting radiation transmitted or reflected from said sample, said detection being carried out by at least a first detection means and a second detection means each containing a plurality of individual detectors, each of said detectors having a peak spectral response distinct from the peak spectral response any other of said detectors in the same detection means, said detectors having an overlap in spectral response with at least one of said other detectors in said same detection means, whereby said first detection means generates a first data stream formed of a composite of a data signal component indicative of said concentration of said constituent and a background component and said second detection means generates a second data stream formed of a composite of a data signal component indicative of said concentration of said constituent and a background component; and

said analysis means compares said first data stream with said second data stream in order to generate an information signal indicative of the concentration of said constituent while rendering the interfering features of the background from said first and second data streams to be less distinct than the background in either data stream individually.

62. The method of claim 61 wherein each of said detectors further comprise an associated filter, each of said associated filters having a peak transmittance or reflectance distinct from the peak transmittance or reflectance of any other of the said filters, each of said filters having an overlap in spectral response with at least one other of said filters.

63. The method of claim 61 wherein said spectrum of illuminating radiation comprises infrared radiation in the 700-2500 nm range.

64. The method of claim 61 wherein said analysis step comprises forming at least two distinct analogs of specific positions in distinct colorimetric spaces from said signals, an n-dimensional space from said first detection means where n is equal to, or less than, the number of detectors in said first detection means, and an m-dimensional space from said second detection means, where m is equal to, or less than, the number of detectors in said second detection means, and correlating said analog positions for said first and second detection means.

65. The method of claim 61 wherein said analysis step is carried out by a neural network.

66. The method of claim 65 wherein said neural network is calibrated and trained to process said signals to achieve an analog of color constancy in human vision.

67. The method of claim 61 wherein said constituent of interest is selected from the group consisting of glucose, glucose indicating constituents, cholesterol, lipids, proteins, hemoglobin and its variants, drugs of abuse, and drugs of abuse indicating constituents.

68. The method of claim 61 wherein said sample comprises a portion of a human body.

69. A method for determining the concentration of a constituent of interest in a sample comprising the steps of:

fixing a portion of said sample of interest in a position such that it can be illuminated with a spectrum of radiation from a radiation source;

illuminating said portion of said sample of interest with a spectrum of radiation from said radiation source;

detecting radiation transmitted or reflected from said sample, said detection being carded out by detection means containing a plurality of individual detectors, each of said detectors having an associated filter which has a peak transmittance or reflectance distinct from the peak transmittance or reflectance any other of said filters, said filters each having overlap in transmittance or reflectance characteristics with at least one of said other filters, at least one of said filters being selected from the group consisting of filters having a spectral response such that it has reflectance or transmittance bands in the portion of the spectrum over which it transmits or reflects radiation, and filters which have only a narrow transmittance or reflectance range;

generating a signal corresponding to said detected radiation from each of said detectors; and

analyzing said signals to obtain a measure of concentration.

70. The method of claim 69 wherein said illuminating radiation comprises infrared radiation in the 700-2500 nm range.

71. The method of claim 69 wherein said analysis step comprises forming an analog of a specific position in an n-dimensional colorimetric space from said signals, where n is equal to, or less than, the number of detectors in said detection means.

72. The method of claim 69 said analysis step is carded out by a neural network.

73. The method of claim 72 wherein said neural network is calibrated and trained to process said signals to achieve an analog of color constancy in vision.

74. The method of claim 69 wherein said constituent of interest is selected from the group consisting of glucose, glucose indicating constituents, cholesterol, lipids, proteins, hemoglobin and its variants, drugs of abuse, and drugs of abuse indicating constituents.

75. The method of claim 69 wherein said sample comprise a portion of a human body.

76. A method for determining the concentration of a constituent of interest in a sample comprising the steps of:

fixing a portion of said sample of interest in a position such that it can be illuminated with a spectrum of radiation from a radiation source;

illuminating said portion of said sample of interest with a spectrum of radiation from a radiation source;

detecting radiation transmitted or reflected from said sample, said detection being carried out by detection means containing a plurality of individual detectors, each of said detectors having a peak spectral response distinct from the peak spectral response of any other of said detectors, said detectors each having overlap in spectral response characteristics with at least one of said other detectors;

collecting outputs from each of said detectors using a interrogation means which has a sufficiently rapid response to observe a distinct arterial pulse such that the data collected can be correlated to arterial blood levels of said constituent of interest;

generating a data signal component corresponding to said collected outputs; and

analyzing said data signal component components to obtain a measure of concentration.

77. The method of claim 76 wherein each of said detectors further comprise an associated filter, each of said associated filters having a peak transmittance or reflectance distinct from the peak transmittance or reflectance of any other of the said filters, each of said filters having an overlap in transmittance or reflectance characteristics with at least one other of said filters.

78. The method of claim 76 wherein said illuminating radiation comprises infrared radiation in the 700-2500 nm range.

79. The method of claim 76 wherein said analysis step comprises forming an analog of a specific position in an n-dimensional colorimetric space from said signals, where n is equal to, or less than, the number of detectors in said detection means.

80. The method of claim 76 wherein said analysis step is carried out by a neural network.

81. The method of claim 80 wherein said neural network is calibrated and trained to process said signals to achieve an analog of color constancy in vision.

82. The method of claim 76 wherein said constituent of interest is selected from the group consisting of glucose, glucose indicating constituents, cholesterol, lipids, proteins, hemoglobin and its variants, drugs of abuse, and drugs of abuse indicating constituents.

83. The method of claim 76 wherein said sample comprises a portion of a human body.

84. The method of claim 76 wherein said detection means comprises a plurality of detection means, each of said detection means having filters associated therewith to generate a distinct signal from any other of said detection means, and wherein said analysis of said signals comprises comparing said signals obtained from each of said detector means.