Non-invasive tissue glucose level monitoring

• US 20020016534A1
• Filed: 02/20/2001
• Published: 02/07/2002
• Est. Priority Date: 04/06/1999
• Status: Active Grant

• Current Assignee: Cercacor Laboratories
• Original Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Trepagnier, Pierre, Kollias, Nikiforos, Mansfield, James, Brand, Derek, Hopmeier, Michael J., Freeman, Jenny
• Granted Patent: US 6,721,582 B2
• Time in Patent Office: Days
• US Class Current: 600/316
• CPC Class Codes: A61B 5/0059 using light, e.g. diagnosis by transillumination, diascopy, fluorescence A61B5/0093, A61B5/1455, A61B5/02416 and A61B5/0261 take precedence
• CPC Class Codes: A61B 5/0062 Arrangements for scanning
• CPC Class Codes: A61B 5/0071 by measuring fluorescence emission
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/1455 using optical sensors, e.g. spectral photometrical oximeters
• CPC Class Codes: A61B 5/443 Evaluating skin constituents, e.g. elastin, melanin, water
• CPC Class Codes: A61B 5/444 Evaluating skin marks, e.g. mole, nevi, tumour, scar
• CPC Class Codes: A61B 5/445 Evaluating skin irritation or skin trauma, e.g. rash, eczema, wound, bed sore

Abstract

Instruments and methods are described for performing non-invasive measurements of analyte levels and for monitoring, analyzing and regulating tissue status, such as tissue glucose levels.

Claims

1. A non-invasive analyte monitoring instrument comprising:

a radiation source for directing excitation radiation to a portion of a surface of a tissue wherein said source emits radiation at least one wavelength that excites a target in said tissue causing said target to emit radiation such that the radiation received at the surface provides an analyte level indication of the patient;

a radiation detector positioned to receive radiation emitted from the surface; and

a processing circuit operatively connected to the radiation detector that translates radiation received at the surface to a measurable signal to obtain said analyte level indication, wherein said radiation source comprises a visible light source or an ultraviolet light source.

2. The instrument of claim 1 wherein the analyte is glucose.

3. The instrument of claim 1 wherein said portion of a tissue surface is at least about 0.5 square centimeters.

4. A non-invasive glucose monitoring instrument comprising:

a radiation source for directing excitation radiation to a portion of a tissue surface wherein said source emits excitation radiation at least one wavelength of ultraviolet or visible light that excites a target to emit radiation, such that the radiation emitted from the excited target and received at the tissue surface correlates with a glucose level of the tissue;

a radiation detector positioned to receive the radiation emitted from the tissue surface; and

analyzing means operatively connected to the radiation detector for analyzing radiation detected by the radiation detector and translating said detected radiation to an indication of the tissue glucose level.

5. The instrument of claim 4 wherein said analyzing means analyzes one or more parameters selected from the group consisting of wavelength of fluorescence, intensity, overall fluorescence, relative peak ratios, spectral shapes, peak shifts, band narrowing, band broadening and combinations thereof.

6. The instrument of claim 4 wherein said analyzing means comprises means for applying one or more multi variate analysis methodologies selected from the group consisting of PLS, PCR, LDA MLR, stepwise LR and combinations thereof.

7. The instrument of claim 4 wherein said radiation source is configured to emit excitation radiation at a plurality of different wavelengths and said radiation detector is configured to synchronously scan radiation emitted by the target with the excitation radiation.

8. The instrument of claim 7 which comprises a sync 50 scan.

9. The instrument of claim 7 which comprises an excitation emission map.

10. The instrument of claim 4 further including a flexible-fiber optic arm that is configured to direct said excitation radiation to the target.

11. The instrument of claim 10 wherein the arm comprises a glass or a quartz fiber.

12. The instrument of claim 10 wherein the arm comprises lens apparatus.

13. The instrument of claim 4 wherein the portion of the tissue surface is a portion of the skin of a patient.

14. The instrument of claim 13 wherein the portion of skin irradiated is about 0.5 to 4 square centimeters.

15. The instrument of claim 4 wherein said radiation source comprises means for applying said radiation source to the tissue surface at a constant pressure.

16. The instrument of claim 4 wherein the excitation wavelength is about 295 nm.

17. The instrument of claim 4 wherein the excitation wavelength is between about 330-370 nm.

18. The instrument of claim 4 where the included excitation wavelengths excite 370 nm and 460 nm.

19. The instrument of claim 4 wherein the target is a structural matrix component.

20. The instrument of claim 4 wherein the target is a cellular component.

21. The instrument of claim 4 wherein the target is a mitochondrial component.

22. The instrument of claim 4 wherein the target is a collagen cross link.

23. The instrument of claim 22 wherein the target is a pepsin-digestible or a collagenase-digestible collagen cross link.

24. The instrument of claim 4 wherein the target is tryptophan-containing proteins.

25. The instrument of claim 4 wherein the target is NADH.

26. The instrument of claim 4 wherein the target is FAD or another flavoprotein.

27. The instrument of claim 4 wherein the target is a combination of fluorophores selected from the group consisting of a pepsin-digestible collagen cross link, a collagenase-digestible collagen cross link, a non-pepsin digestible collagen cross link, tryptophan-containing proteins, elastin cross links, FAD and NADH.

28. The instrument of claim 4 wherein the radiation received at the surface has been quenched or amplified by one or more matrix, cellular, or mitochondrial components, or any other cellular component reflective of metabolic activity, in the tissue.

29. The instrument of claim 4 wherein the radiation received at the surface has been quenched or amplified by a fluorescent cellular energy component or a shift in equilibrium of said cellular energy component.

30. The instrument of claim 4 wherein the radiation source is operative to emit radiation at between about 285 and 305 nm and the radiation detector is operative to detect radiation at between about 315 and 420 nm.

31. The instrument of claim 4 wherein the radiation source is operative to emit radiation at between about 330 and 345 nm and the radiation detector is operative to detect radiation at between about 370 and 410 nm.

32. The instrument of claim 4 wherein the radiation source is operative to emit radiation at between about 330 and 360 nm and the radiation detector is operative to detect radiation at between about 400 and 550 nm.

33. The instrument of claim 4 wherein the radiation source is operative to emit radiation at between about 330 and 500 nm and the radiation detector is operative to detect radiation at between about 500 and 560 nm.

34. The instrument of claim 4 further comprising a display operatively connected to the analyzing means that is operative to display said glucose level indication.

35. The instrument of claim 4 wherein said analyzing means further comprises means for monitoring a trend in glucose levels and said instrument further comprises a device responsive to the analyzing means that is operative to administer a medication to a patient at a rate that corresponds to the indicated glucose level.

36. The instrument of claim 35 wherein the medication is glucose or insulin and the device is a pump.

37. The instrument of claim 4 further comprising an alarm means operationally coupled to the analyzing means wherein the alarm means is activated when the indicated glucose concentration exceeds a first predetermined value, falls below a second predetermined value or varies more than a predetermined amount from a third predetermined value.

38. The instrument of claim 37 wherein the first, second or third predetermined value is 20%.

39. The instrument of claim 4 further comprising a normalizing detector responsive to another target that provides normalizing information to said processing circuit to normalize the indicated glucose level.

40. The instrument of claim 4 further comprising normalizing means which provides normalizing information to said analyzing means to normalize the indicated glucose level.

41. The instrument of claim 40 wherein said normalizing means normalizes for age, UV damage, skin color, temperature, perfusion, hydration, pH and combinations thereof.

42. The instrument of claim 4 further comprising means for measuring scattering.

43. The instrument of claim 42 wherein the means for measuring scattering comprises an illuminating means that emits radiation at an angle greater than 60 degrees to said target.

44. The instrument of claim 42 wherein the means for measuring scattering comprises an illuminating means which emits radiation at between about 330 to 420 nm.

45. The instrument of claim 42 wherein the means for measuring scattering comprises an illuminating means which emits radiation at between about 320 to 800 nm.

46. The instrument of claim 42 further comprising means for measuring absorbance and wherein said analyzing means comprises means for adjusting the indicated glucose concentration based on the scattering and absorbance measured.

48. The method of claim 47 wherein the target is excited with electromagnetic radiation.

49. The method of claim 47 wherein the excitation radiation is at a wavelength of about 295 nm.

50. The method of claim 47 wherein the excitation radiation is at a wavelength of about 335-340 nm.

51. The method of claim 47 wherein the excitation radiation is at two wavelengths of about 370 and 460 nm.

52. The method of claim 47 wherein the excitation radiation is at a wavelength of about 590 nm.

53. The method of claim 47 wherein the excitation radiation is at a wavelength of about 670-680 nm.

54. The method of claim 47 wherein the excitation radiation is at two wavelengths of about 740 and 920 nm.

55. The method of claim 47 wherein the excitation radiation is a combination of subsets of the region of 280-1,100 nm.

56. The method of claim 47 wherein the radiation emitted by the target is fluorescent radiation.

57. The method of claim 47 wherein the target is selected from the group consisting of a pepsin-digestible collagen cross link, a collagenase-digestible collagen cross link, a non-pepsin digestible collagen cross link, tryptophan-containing proteins, elastin cross links, FAD, flavoproteins, NADH and combinations thereof.

58. The method of claim 47 wherein the radiation detected from the excited target is between about 340 and 400 nm.

59. The method of claim 47 wherein the radiation detected from the excited target is between about 400 and 550 nm.

60. The method of claim 47 wherein the radiation detected from the excited target is between about 500 and 560 nm.

61. The method of claim 47 wherein the radiation detected from the excited target is a combination of subsets of the region of 340-560 nm.

62. The method of claim 47 further comprising adjusting the glucose level of the patient in response to the glucose level or trend determined.

63. The method of claim 47 further comprising administering insulin to the patient.

64. The method of claim 63 wherein insulin is administered with a biodelivery system.

65. The method of claim 47 further comprising normalizing the glucose level determined.

66. The method of claim 65 wherein normalizing comprises normalizing for one or more variables selected from the group consisting of temperature, degree of perfusion, age, UV damage, skin color temperature, hydration, and pH.

67. The method of claim 47 further comprising actuating an alarm in response to the glucose level when said glucose level exceeds a predetermined first level, falls below a predetermined second level or varies more than a predetermined amount from a predetermined third level.

68. The instrument of claim 67 wherein the first, second or third predetermined value is 20%.

69. The method of claim 47 further comprising measuring scattering and absorbance and adjusting the glucose level.

70. The method of claim 47 wherein said step of determining the glucose level comprises analyzing the radiation detected using one or more multi variate analysis methodologies selected from a group comprising PLS, PCR, LDA, MLR, stepwise LR and combinations thereof.

71. The method of claim 47 wherein said step of exciting comprises irradiating a target with excitation radiation at a plurality of wavelengths and the step of detecting radiation comprises the step of synchronously scanning the emitted radiation and excitation radiation.

72. The method of claim 47 wherein the step of exciting comprises application of a probe to the skin, said probe comprising a radiation source.

73. The method of claim 72 wherein a position of the probe on the skin is varied during detecting.

47. A non-invasive method of detecting a glucose level of a tissue comprising:

exciting a non-glucose target in the tissue with ultraviolet radiation or visible light wherein the excited target is emits radiation such that the radiation received at a tissue surface is indicative of a glucose level of a patient;

detecting radiation emitted by the target and transmitted through the intervening tissue to the surface; and

determining said glucose level from the radiation detected.

74. A method for detecting diabetes in a patient comprising;

exciting a non-glucose target using ultraviolet and visible radiation;

detecting radiation emitted by the target;

determining said glucose level from the radiation detected; and

detecting diabetes based on said determined glucose level.

75. An instrument for assessing changes in a structural matrix, cellular, or mitochondrial of the skin of a patient comprising:

means for measuring fluorescence emitted from the skin;

means for measuring scattering; and

means for measuring absorbance.

76. The instrument of claim 75 further comprising means for irradiating the tissue with a plurality of wavelengths of excitation light and means for synchronously scanning the fluorescence emitted from the skin with the excitation light.

77. The instrument of claim 75 wherein said means for measuring fluorescence comprises measuring one or more parameters selected from the group consisting of wavelength of fluorescence, intensity, overall fluorescence, relative peak ratios, spectral shapes, peak shifts, band narrowing, band broadening and combinations thereof.

79. The method of claim 78 wherein the step of detecting fluorescence comprises detecting one or more parameters selected from the group consisting of wavelength of fluorescence, intensity, overall fluorescence, relative peak ratios, spectral shapes, peak shifts, band narrowing, band broadening and combinations thereof.

80. The method of claim 79 wherein said change correlates with a condition.

81. The method of claim 80 wherein the condition is selected from the group consisting of cancer, age, diabetes, photodamage, presence of topical steroids and infections.

82. The method of claim 78 further comprising detecting absorbance.

83. The method of claim 78 wherein the first wavelength is between about 320 and 420 nm.

84. The method of claim 78 wherein the second wavelength is between about 330 and 420 nm.

85. The method of claim 78 wherein the first wavelength and the second wavelength are the same.

86. The method of claim 78 wherein the wavelength region is a subset of the region of 280-800 nm.

87. The method of claim 78 wherein the tissue is skin or mucosa.

78. A non-invasive method of assessing a change in the structural matrix, cellular, or mitochondrial of a tissue comprising:

exposing the tissue to radiation at a first wavelength;

detecting fluorescence emitted by exposed tissue;

exposing the tissue to radiation of a second wavelength;

detecting a scattering re-emitted from the exposed tissue; and

deriving an indication representative of the change in the structural matrix of the tissue based on the fluorescence detected and the scattering detected.

88. An instrument for assessing changes in the environment of the matrix, cellular, or mitochondrial components, or other cellular components reflective of metabolic activity, of a tissue comprising:

means for measuring fluorescence;

means for measuring scattering; and

means for measuring absorbance.

89. A non-invasive method of assessing a change in the environment of the matrix, cellular, or mitochondrial components, or other cellular components reflective of metabolic activity, of a tissue comprising:

exposing the tissue to radiation at a first wavelength;

detecting fluorescence emitted by exposed tissue;

exposing the tissue to radiation of a second wavelength;

detecting scattering re-emitted from the exposed tissue;

detecting absorbance; and

deriving an indication representative of the change in the environment of the matrix, cellular, or mitochondrial components, or other cellular components reflective of metabolic activity, of the tissue based on the fluorescence detected, the scattering detected and the absorbance detected.

90. A non-invasive method for monitoring skin or tissue constituents in which information about or signature of a specific blood analyte level or disease process is provided comprising the steps of:

exciting a target fluorophore;

detecting radiation emitted by the fluorophore and transmitted through intervening tissue to the surface; and

determining said information or signature from the radiation detected.