Non-invasive glucose monitor

• US 6,181,957 B1
• Filed: 07/12/1999
• Issued: 01/30/2001
• Est. Priority Date: 07/13/1998
• Status: Expired due to Term

• Current Assignee: California Institute of Technology, Childrens Hospital Los Angeles
• Original Assignee: California Institute of Technology, Childrens Hospital Los Angeles
• Inventors: Borchert, Mark S., Lambert, James L.
• Primary Examiner(s): WINAKUR, ERIC FRANK
• Application Number:
  US09/351,788
• Time in Patent Office: 568 Days
• Field of Search: 600/310, 600/316, 600/317, 600/318, 600/319
• US Class Current: 600/319
• CPC Class Codes: A61B 5/0002 Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network A61B5/07 takes precedence; transmission systems for measured values G08C; transmission H04B; transmission of digital information H04L; wireless communication networks H04W
• 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

Abstract

A non-invasive method for determining blood level of an analyte of interest, such as glucose, comprises: generating an excitation laser beam (e.g., at a wavelength of 700 to 900 nanometers); focusing the excitation laser beam into the anterior chamber of an eye of the subject so that aqueous humor in the anterior chamber is illuminated; detecting (preferably confocally detecting) a Raman spectrum from the illuminated aqueous humor; and then determining the blood glucose level (or the level of another analyte of interest) for the subject from the Raman spectrum. Preferably, the detecting step is followed by the step of subtracting a confounding fluorescence spectrum from the Raman spectrum to produce a difference spectrum; and determining the blood level of the analyte of interest for the subject from that difference spectrum, preferably using linear or nonlinear multivariate analysis such as partial least squares analysis. Apparatus for carrying out the foregoing method is also disclosed.

Claims

1. A non-invasive method for determining blood glucose levels in a subject, comprising:

generating an excitation laser beam at a wavelength of from 700 to 900 nanometers;

focusing said excitation laser beam into the anterior chamber of an eye of said subject so that aqueous humor in said anterior chamber is illuminated;

detecting a Raman spectrum from said illuminated aqueous humor;

subtracting a fluorescence spectrum for said aqueous humor from said Raman spectrum to produce a difference spectrum; and

then

determining the blood glucose level for said subject from said difference spectrum.

2. A method according to claim 1, wherein said laser beam pulse has a duration not greater than thirty seconds.

3. A method according to claim 1, wherein said laser beam pulse has an instantaneous power not greater than 30 milliwatts.

4. A method according to claim 1, wherein said focusing step is carried out so that energy on the retina of said eye from said excitation laser beam pulse is not greater than 3000 milliwatts per square centimeter.

5. A method according to claim 1, further comprising the step of subtracting the spectrum of adjacent tissues from said Raman spectrum.

6. A method according to claim 1, wherein said subject is a human subject.

7. A method according to claim 1, wherein said determining step is carried out with an empirical model of actual testing experience.

8. A method according to claim 7, wherein said empirical model is generated by multivariate analysis.

9. A method according to claim 8, wherein said multivariate analysis is a partial least squares analysis.

10. A method according to claim 7, wherein:

said empirical model is produced with a training set comprising at least 20 aqueous humor samples, a Raman spectra corresponding to each of said samples, and a blood glucose level corresponding to each of said samples;

with the concentration of glucose in either the aqueous humor samples or corresponding blood samples varying by at least 200 mg/dL from the sample with the lowest concentration to the sample with the highest concentration.

11. A method according to claim 10, wherein the concentration of the principle Raman-active compounds in said samples vary substantially non-colinearly among said samples.

12. An apparatus for the non-invasive determination of a blood level of an analyte of interest in a subject, comprising:

a laser for generating an excitation laser beam;

an optical system operatively associated with said laser for directing said excitation laser beam into the anterior chamber of an eye of said subject so that aqueous humor in said anterior chamber is sufficiently illuminated to detect Raman scattered light;

a detector operatively associated with said optical system and configured to detect a Raman spectrum from said aqueous humor;

means for subtracting a fluorescence spectrum for said aqueous humor from said Raman spectrum to produce a difference spectrum; and

a processor for determining the blood level of said analyte of interest for said subject from said difference spectrum; and

a display target projected through said optical system that visually displays said blood level of said analyte of interest.

13. An apparatus according to claim 12, further comprising a fixation target operatively associated with and projected through said optical system to assure proper direction and focusing of the laser beam into the anterior chamber of the eye.

14. An apparatus according to claim 12, wherein said optical system is a confocal optical system.

15. An apparatus according to claim 12, wherein said laser beam has a wavelength of from 700 to 900 nanometers.

16. An apparatus for the non-invasive determination of a blood level of an analyte of interest in a subject, comprising:

a laser for generating an excitation laser beam;

an optical system operatively associated with said laser for directing said excitation laser beam into the anterior chamber of an eye of said subject so that aqueous humor in said anterior chamber is illuminated sufficiently to detect Raman scattered light;

a detector operatively associated with said optical system and configured to detect a Raman spectrum from said aqueous humor;

means for subtracting a fluorescence spectrum for said aqueous humor from said Raman spectrum to produce a difference spectrum;

a processor for determining the blood level of said analyte of interest for said subject from said difference spectrum, said processor including an empirical model of actual testing experience.

17. An apparatus according to claim 16, wherein said empirical model is generated by multivariate analysis.

18. An apparatus according to claim 17, wherein said multivariate analysis is a partial least squares analysis.

19. An apparatus according to claim 16, wherein:

said empirical model is produced with a training set comprising at least 20 aqueous humor samples, a Raman spectra corresponding to each of said samples, and a blood level of said analyte of interest corresponding to each of said samples;

with the concentration of said analyte of interest in either the aqueous humor samples or corresponding blood samples varying by at least a factor of 5 from the sample with the lowest concentration to the sample with the highest concentration.

20. An apparatus according to claim 16, further comprising a communication line connected to said processor for transmitting said blood level of said analyte of interest to a remote location.

21. An apparatus according to claim 16, wherein said optical system is a confocal optical system.

22. An apparatus according to claim 16, wherein said laser beam has a wavelength of from 700 to 900 nanometers.

23. An apparatus according to claim 16, wherein said analyte of interest is glucose.

24. An apparatus for the non-invasive determination of a blood level of an analyte of interest in a subject, comprising:

laser means for generating a plurality of excitation laser beams at a plurality of different wavelengths;

an optical system operatively associated with said laser means and configured to direct said excitation laser beams into the anterior chamber of an eye of said subject so that aqueous humor in said anterior chamber is sufficiently illuminated to detect Raman scattered light;

detector means operatively associated with said optical system and configured to detect a Raman spectrum from said aqueous humor at a plurality of detector wavelengths;

control means operatively associated with said laser means for sliding said Raman spectrum through said plurality of detector wavelengths;

means for subtracting a fluorescence spectrum for said aqueous humor from said Raman spectrum to produce a difference spectrum; and

a processor for determining the blood level of said analyte of interest for said subject from said difference spectrum.

25. An apparatus according to claim 24, wherein said laser means comprises a tunable laser.

26. An apparatus according to claim 24, wherein said laser means comprises a plurality of fixed frequency lasers.

27. An apparatus according to claim 24, wherein said optical system is a confocal optical system.