Apparatus for non-invasive analyses of biological compounds

• US 5,657,754 A
• Filed: 07/10/1995
• Issued: 08/19/1997
• Est. Priority Date: 07/10/1995
• Status: Expired due to Fees

• Current Assignee: Allan Rosencwaig
• Original Assignee: Allan Rosencwaig
• Inventors: Rosencwaig, Allan
• Primary Examiner(s): Sykes, Angela D.
• Assistant Examiner(s): HUANG, STEPHEN D
• Application Number:
  US08/500,120
• Time in Patent Office: 771 Days
• Field of Search: 128/633, 128/664, 128/665
• US Class Current: 600/316
• 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: G01N 21/171 with calorimetric detection, e.g. with thermal lens detection
• CPC Class Codes: G01N 21/19 Dichroism
• CPC Class Codes: G01N 25/00 Investigating or analyzing materials by the use of thermal means G01N3/00 - G01N23/00 take precedence

Abstract

An apparatus for the non-invasive analysis of non-homogeneous samples is disclosed. The apparatus is particularly suited for analyzing biological samples having different constituents. An intensity modulated light beam is used to preferentially heat a selected constituent in the sample. This periodic heating will create thermal waves in the sample. A probe beam is directed to interact with the sample in the region which has been periodically heated. A phase synchronous detector is used to monitor the periodic changes in the probe beam caused by the thermal waves in the sample. In the preferred embodiment for monitoring blood glucose levels, the wavelength of the modulated light beam is selected to be absorbed in the hemoglobin of the red blood cells. The modulation frequency of the light beam is selected to set the thermal diffusion length of the thermal waves to permit interaction with the glucose molecules in the blood plasma. In addition, the phase synchronous detector is configured to monitor signals which occur ninety degrees out of phase with the modulation of the heating beam. In this manner, the output from the system can be most accurately targeted to the constituent of interest.

Claims

1. An apparatus for analyzing properties of a sample, said sample being non-homogeneous and including at least first and second constituents, said apparatus comprising:

means for selectively inducing a periodic heating at a predetermined frequency in said first constituents in the sample in a manner to create thermal waves therein and wherein said predetermined frequency is selected to substantially confine the thermal waves to the first constituents when the properties of said first constituent are to be analyzed, and wherein the predetermined frequency is selected so that the thermal waves will spread out to reach the second constituents when the properties of the second constituents are to be analyzed;

a phase synchronous detector for monitoring periodic effects of the thermal waves on the sample and generating an output signal, and wherein the portion of the output signal which is in phase with respect to the periodic heating will be primarily from the first constituents while the portion of the output signal which is ninety degrees out of phase with the periodic heating will be primarily from the second constituents when the predetermined frequency has been selected so that the thermal waves spread out to reach the second constituents; and

processor means for analyzing the sample based on the output signal generated by said detector and with the frequency of the periodic heating and the phase of the output signal of the detector with respect to the periodic heating being selected to target the analysis to one of the first or second constituents in the sample.

2. An apparatus as recited in claim 1 wherein the frequency of the periodic heating is selected so that the spread of the thermal waves is primarily confined to the first constituents.

3. An apparatus as recited in claim 1 wherein the detector is configured to monitor periodic effects of the thermal waves which are in-phase with the periodic heating.

4. An apparatus as recited in claim 3 wherein the detector is configured to also monitor periodic effects of the thermal waves which are approximately ninety degrees out of phase with the periodic heating and wherein the out-of-phase signals are used to normalize the in-phase signals.

5. An apparatus as recited in claim 1 wherein the frequency of the periodic heating means is selected so that the thermal waves will spread and interact with the second constituents.

6. An apparatus as recited in claim 5 wherein the detector is configured to monitor periodic effects of the thermal waves which are approximately ninety degrees out of phase with the periodic heating permitting targeting of the second constituent.

7. An apparatus as recited in claim 6 wherein the frequency of the periodic heating means is selected so that the thermal diffusion length of the thermal waves will be equal to approximately half an average distance between the first constituents.

8. An apparatus as recited in claim 6 wherein the frequency of the periodic heating means is selected so that the thermal diffusion length of the thermal waves will be equal to approximately (2/π

) times the average distance between the first and second constituents.

9. An apparatus as recited in claim 1 wherein said periodic heating means includes:

a light source for generating a pump beam having a wavelength which is preferentially absorbed in said first constituents of said sample;

means for intensity modulating said pump beam at a predetermined frequency; and

means for directing the pump beam to the sample so that the energy of the pump beam is absorbed in said first constituents in a manner to generate thermal waves emanating therefrom.

10. An apparatus as recited in claim 1 wherein said detector includes an ultrasonic imager.

11. An apparatus as recited in claim 1 wherein said detector includes a microwave generator and detector.

12. An apparatus as recited in claim 1 wherein said detector includes a magnetic resonance imager.

13. An apparatus as recited in claim 1 wherein said detector includes a light source for generating a probe beam and a means for directing the probe beam to interact with the sample.

14. An apparatus as recited in claim 13 wherein the wavelength of the probe beam is selected to be preferentially absorbed in the targeted constituent.

15. An apparatus as recited in claim 13 wherein the detector functions to measure modulated changes in power of the probe beam after it has interacted with the sample.

16. An apparatus as recited in claim 13 wherein the detector functions to measure modulated changes in reflected power of the probe beam.

17. An apparatus as recited in claim 13 wherein the detector functions to measure modulated changes in transmitted power of the probe beam.

18. An apparatus as recited in claim 13 wherein the detector functions to measure modulated changes in scattering of the probe beam.

19. An apparatus as recited in claim 13 wherein the detector functions to measure modulated changes in a polarization state of the probe beam.

20. An apparatus for a non-invasive, in vivo analysis of constituents carried in blood of a living mammal, said blood including red blood cells having hemoglobin therein, said apparatus comprising:

a first light source for generating a pump beam having a wavelength which is preferentially absorbed in the hemoglobin of red blood cells;

means for intensity modulating said pump beam at a predetermined frequency;

means for directing the pump beam through a skin of the mammal and into the blood so that the energy of the pump beam is absorbed in the red blood cells in a manner to generate thermal waves emanating therefrom;

a second light source for generating a probe beam;

means for directing the probe beam through the skin of the animal and into the blood;

a phase synchronous detector for monitoring the periodic changes in the probe beam caused by the thermal waves in the blood and generating an output signal; and

processor means for analyzing the constituents in the blood based on the output signal generated by said detector and with the modulation frequency of the pump beam and the phase of the output signal of the detector with respect to the periodic heating being selected to target the analysis to selected constituents in the sample.

21. An apparatus as recited in claim 20 wherein the frequency of the periodic heating is selected so that the spread of the thermal waves is primarily confined to the red blood cells.

22. An apparatus as recited in claim 20 wherein the detector is configured to monitor periodic effects of the thermal waves which are in-phase with the periodic heating.

23. An apparatus as recited in claim 22 wherein the detector is configured to also monitor periodic effects of the thermal waves which are approximately ninety degrees out of phase with the periodic heating and wherein the out-of-phase signals are used to normalize the in-phase signals.

24. An apparatus as recited in claim 20 wherein the frequency of the periodic heating means is selected so that the thermal waves will spread beyond the hemoglobin to other constituents in the blood.

25. An apparatus as recited in claim 24 wherein the detector is configured to monitor periodic effects of the thermal waves which are approximately ninety degrees out of phase with the periodic heating permitting targeting of the other constituents in the blood.

26. An apparatus as recited in claim 25 wherein the frequency of the periodic heating means is selected so that the thermal diffusion length of the thermal waves will be equal to approximately half an average distance between the red blood cells.

27. An apparatus as recited in claim 20 wherein the wavelength of the probe beam is selected to be preferentially absorbed in the targeted constituent.

28. An apparatus as recited in claim 20 wherein the detector functions to measure modulated changes in power of the probe beam after it has interacted with the sample.

29. An apparatus as recited in claim 28 wherein the detector functions to measure modulated changes in reflected power of the probe beam.

30. An apparatus as recited in claim 28 wherein the detector functions to measure modulated changes in transmitted power of the probe beam.

31. An apparatus as recited in claim 20 wherein the detector functions to measure modulated changes in scattering of the probe beam.

32. An apparatus as recited in claim 20 wherein the detector functions to measure modulated changes in a polarization state of the probe beam.

33. An apparatus as recited in claim 20 wherein the targeted constituent is glucose and wherein said probe beam is linearly polarized prior to interacting with the glucose and wherein said detector monitors the modulated polarization rotation of the beam.

34. An apparatus as recited in claim 33 wherein the wavelength of the probe beam is selected to be in the visible region.

35. An apparatus as recited in claim 20 wherein the targeted constituent is glucose and wherein said probe beam is alternately left and right-hand circularly polarized prior to interacting with the blood stream and wherein said detector monitors a modulated ratio of transmitted left and right-hand circular polarized light of the probe beam.

36. An apparatus as recited in claim 35 wherein the wavelength of the probe beam is selected to be in a near infrared range.

37. An apparatus for non-invasive, in vivo analysis of glucose carried in a blood stream of a living mammal, said blood stream also carrying red blood cells having hemoglobin therein, said apparatus comprising:

a first light source for generating a pump beam having a wavelength which is preferentially absorbed in the hemoglobin of red blood cells;

means for intensity modulating said pump beam at a predetermined frequency;

means for directing the pump beam through a skin of the mammal and into the blood stream so that the energy of the pump beam is absorbed in the red blood cells in a manner to generate thermal waves emanating therefrom, with the modulation frequency of the pump beam being selected so that the thermal waves extend beyond the hemoglobin and interact with the glucose in the blood stream;

a second light source for generating a probe beam;

means for directing the probe beam through the skin of the mammal and into the blood stream;

a phase synchronous detector for monitoring periodic changes in the probe beam caused by the thermal waves interacting with the glucose in the blood stream and generating an output signal responsive thereto, said detector for monitoring the periodic changes in the probe beam that are approximately ninety degrees out of phase with respect to the thermal waves; and

processor means for analyzing a concentration of glucose in the blood stream based on the output signal generated by said detector.

38. An apparatus as recited in claim 37 wherein the modulation frequency of the pump beam is selected so that the thermal diffusion length of the thermal waves will be equal to approximately half the average distance between red blood cells.

39. An apparatus as recited in claim 37 wherein said probe beam is linearly polarized prior to interacting with the glucose and wherein said detector monitors modulated changes in a polarization rotation of the beam.

40. An apparatus as recited in claim 39 wherein the wavelength of the probe beam is selected to be in the visible range.

41. An apparatus as recited in claim 39 wherein said probe beam is alternately left and right-hand circularly polarized prior to interacting with the blood stream and wherein said detector monitors a modulated ratio of the transmitted left and right-hand circular polarized light of the probe beam.

42. An apparatus as recited in claim 41 wherein the wavelength of the probe beam is selected to be in a near infrared range.

43. An apparatus as recited in claim 37 wherein the wavelength of the pump beam is between 400 and 600 nm.

44. An apparatus as recited in claim 37 wherein the modulation frequency of the pump beam is on an order of 10 kHz.

45. An apparatus as recited in claim 37 wherein the detector functions to measure modulated changes in transmitted power of the probe beam.

46. An apparatus as recited in claim 45 wherein the wavelength of the probe beam is selected to be in the visible range.

47. A method for analyzing properties of a sample, said sample being non-homogenous and including at least first and second constituents, said method comprising the steps of:

generating a pump beam having a wavelength which is preferentially absorbed in the first constituents, said pump beam being intensity modulated with a predetermined frequency;

directing the pump beam to interact with the sample to selectively induce a periodic heating in the first constituents in a manner to generate thermal waves emanating therefrom, and wherein the modulation frequency of the pump beam is selected so that the thermal waves extend beyond the first constituents and interact with the second constituents;

generating a probe beam;

directing the probe beam to interact with the sample;

monitoring periodic changes in the probe beam caused by the thermal waves interacting with the second constituents and generating an output signal responsive thereto, and with the monitored periodic changes being approximately ninety degrees out of phase with the periodicity of the thermal waves; and

analyzing the second constituents in the sample based on the output signal.

48. A method as recited in claim 47 wherein the modulation frequency of the pump beam is selected so that the thermal diffusion length of the thermal waves will be equal to approximately half the average distance between the first constituents.

49. A method as recited in claim 47 wherein the modulation frequency of the pump beam is selected so that the thermal diffusion length of the thermal waves will be equal to approximately (2/π

) times the average distance between the first and second constituents.

50. A method as recited in claim 47 wherein modulated changes in power of the probe beam are monitored after it has interacted with the sample.

51. A method as recited in claim 47 wherein modulated changes in reflected power of the probe beam are monitored.

52. A method as recited in claim 47 wherein modulated changes in transmitted power of the probe beam are monitored.

53. A method as recited in claim 47 wherein modulated changes in scattering of the probe beam are monitored.

54. A method as recited in claim 47 wherein modulated changes in a polarization state of the probe beam are monitored.

55. A method as recited in claim 47 wherein the sample is blood and the first constituent is hemoglobin and the second constituent is glucose and wherein said probe beam is linearly polarized prior to interacting with the glucose and wherein the modulated polarization rotation of the beam is monitored.

56. A method as recited in claim 47 wherein the sample is blood and the first constituent is hemoglobin and the second constituent is glucose and wherein said probe beam is alternately left and right-hand circularly polarized prior to interacting with the blood stream and wherein a modulated ratio of the transmitted left and right-hand circular polarized light of the probe beam is monitored.

57. A method for a non-invasive, in vivo analysis of glucose carried in a blood stream of a living mammal, said blood stream also carrying red blood cells having hemoglobin therein, said method comprising the steps of:

generating a pump beam having a wavelength which is preferentially absorbed in the hemoglobin of red blood cells;

intensity modulating said pump beam at a predetermined frequency;

directing the pump beam through a skin of the mammal and into the blood stream so that the energy of the pump beam is absorbed in the red blood cells in a manner to generate thermal waves emanating therefrom, with the modulation frequency of the pump beam being selected so that the thermal waves extend beyond the hemoglobin and interact with the glucose in the blood stream;

generating a probe beam;

directing the probe beam through the skin of the mammal and into the blood stream;

monitoring periodic changes in the probe beam caused by the thermal waves interacting with the glucose in the blood stream and generating an output signal responsive thereto, and with the monitored periodic changes in the probe beam being approximately ninety degrees out of phase with the periodicity of the thermal waves; and

analyzing a concentration of glucose in the blood stream based on the output signal generated by said detector.

58. A method as recited in claim 57 wherein the modulation frequency of the pump beam is selected so that the thermal diffusion length of the thermal waves will be equal to approximately half the average distance between red blood cells.

59. A method as recited in claim 57 wherein the probe beam is linearly polarized prior to interacting with the glucose and wherein modulated changes in polarization rotation of the beam are monitored.

60. A method as recited in claim 59 wherein the wavelength of the probe beam is selected to be in a visible region.

61. A method as recited in claim 57 wherein said probe beam is alternately left and right-hand circularly polarized prior to interacting with the blood stream and wherein a modulated ratio of the transmitted left and right-hand circular polarized light is monitored.

62. A method as recited in claim 61 wherein the wavelength of the probe beam is selected to be in a near infrared range.

63. A method as recited in claim 57 wherein the wavelength of the pump beam is between 400 and 600 nm.

64. A method as recited in claim 57 wherein the modulation frequency of the pump beam is on an order of 10 kHz.

65. A method as recited in claim 57 wherein modulated changes in transmitted power of the probe beam are monitored.

66. A method as recited in claim 65 wherein the wavelength of the probe beam is selected to be in a visible range.

67. An apparatus for analyzing properties of a sample, said sample being non-homogenous and including at least first and second constituents, said apparatus comprising:

a first light source for generating a pump beam having a wavelength which is preferentially absorbed in the first constituents, said pump beam being intensity modulated with a predetermined frequency;

means for directing the pump beam to interact with the sample to selectively induce a periodic heating in the first constituents in a manner to generate thermal waves emanating therefrom, and wherein the modulation frequency of the pump beam is selected so that the thermal waves extend beyond the first constituents and interact with the second constituents;

a second light source for generating a probe beam;

means for directing the probe beam to interact with the sample;

a phase synchronous detector for monitoring periodic changes in the probe beam caused by the thermal waves interacting with the second constituents and generating an output signal responsive thereto, and with the monitored periodic changes being approximately ninety degrees out of phase with respect to the thermal waves; and

a processor for analyzing the second constituents in the sample based on the output signal from the detector.

68. An apparatus as recited in claim 67 wherein modulated changes in transmitted power of the probe beam are monitored.

69. An apparatus as recited in claim 67 wherein modulated changes in the polarization state of the beam are monitored.

70. An apparatus as recited in claim 67 wherein said probe beam is alternately left and right-hand circularly polarized prior to interacting with the sample and wherein said detector monitors a modulated ratio of the transmitted left and right-hand circular polarized light of the probe beam.

71. A method for analyzing properties of a sample, said sample being non-homogeneous and including at least first and second constituents, said apparatus comprising:

selectively inducing a periodic heating at a predetermined frequency in said first constituents in the sample in a manner to create thermal waves therein and wherein said predetermined frequency is selected to substantially confine the thermal waves to the first constituents when the properties of said first constituent are to be analyzed, and wherein the predetermined frequency is selected so that the thermal waves will spread out to reach the second constituents when the properties of the second constituents are to be analyzed;

monitoring periodic effects of the thermal waves on the sample and generating an output signal, and wherein the portion of the output signal which is in phase with respect to the periodic heating will be primarily from the first constituents while the portion of the output signal which is ninety degrees out of phase with the periodic heating will be primarily from the second constituents when the predetermined frequency has been selected so that the thermal waves spread out to reach the second constituents; and

analyzing the sample based on the output signal and with the frequency of the periodic heating and the phase of the output signal with respect to the periodic heating being selected to target the analysis to one of the first or second constituents in the sample.

72. A method as recited in claim 71 wherein the frequency of the periodic heating is selected so that the spread of the thermal waves is primarily confined to the first constituents.

73. A method as recited in claim 71 wherein periodic effects of the thermal waves which are in-phase with the periodic heating are monitored.

74. A method as recited in claim 73 wherein periodic effects of the thermal waves which are approximately ninety degrees out of phase with the periodic heating are monitored and wherein the out-of-phase signals are used to normalize the in-phase signals.

75. A method as recited in claim 71 wherein the frequency of the periodic heating is selected so that the thermal waves will spread and interact with the second constituents.

76. A method as recited in claim 75 wherein the periodic effects of the thermal waves which are approximately ninety degrees out of phase with the periodic heating are monitored permitting targeting of the second constituent.

77. A method as recited in claim 76 wherein the frequency of the periodic heating is selected so that the thermal diffusion length of the thermal waves will be equal to approximately half an average distance between the first constituents.

78. A method as recited in claim 76 wherein the frequency of the periodic heating is selected so that the thermal diffusion length of the thermal waves will be equal to approximately (2/π

) times an average distance between the first and second constituents.