Method for non-invasive measurement of an analyte

• US 6,044,285 A
• Filed: 11/12/1998
• Issued: 03/28/2000
• Est. Priority Date: 11/12/1997
• Status: Expired due to Term

• Current Assignee: Lightouch Medical, Inc.
• Original Assignee: Lightouch Medical, Inc.
• Inventors: Chaiken, Joseph, Peterson, Charles M.
• Primary Examiner(s): WINAKUR, ERIC FRANK
• Application Number:
  US09/191,478
• Time in Patent Office: 502 Days
• Field of Search: 600/310, 600/316, 600/322, 600/476, 356/39, 356/301
• 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: A61B 5/14553 specially adapted for cerebral tissue
• CPC Class Codes: G01N 21/49 within a body or fluid
• CPC Class Codes: G01N 21/65 Raman scattering

Abstract

Disclosed is a method and apparatus for measuring an analyte in a tissue of a subject. The method comprises contacting the tissue with electromagnetic radiation having a first excitation wavelength, wherein the first excitation wavelength is substantially equal to an absorption wavelength of a temperature probe within the tissue. The temperature probe and the analyte are sufficiently proximate to one another that energy deposited into one by absorption of radiation is transferred to the other. The Raman spectra emitted by the tissue are collected and analyzed to determine a concentration of analyte present in the tissue. The analysis can comprise measuring the Raman spectra associated with the temperature probe. In addition, the method can include simultaneously contacting the tissue with electromagnetic radiation having the first excitation wavelength and with electromagnetic radiation having a second excitation wavelength, wherein the second excitation wavelength is substantially equal to an absorption wavelength of the analyte. The analysis comprises comparing the spectra emitted in response to the first excitation wavelength in the presence and in the absence of the second excitation wavelength. In another embodiment, the analysis comprises measuring the anti-Stokes component of the Raman spectra associated with the analyte. The method provides a non-invasive measurement of blood glucose, using hemoglobin as the temperature probe.

Claims

1. A method of measuring an analyte in a tissue of a subject comprising:

(a) contacting the tissue with electromagnetic radiation having a first excitation wavelength, wherein the first excitation wavelength is substantially equal to an absorption wavelength of a temperature probe within the tissue, and wherein the temperature probe and the analyte are sufficiently proximate to one another that energy deposited into one by absorption of radiation is transferred to the other;

(b) collecting the Raman spectra emitted by the tissue; and

(c) analyzing the collected spectra to determine a concentration of the analyte present in the tissue.

2. The method of claim 1, wherein the analyzing comprises measuring the Raman spectra associated with the temperature probe.

3. The method of claim 2, further comprising simultaneously contacting the tissue with electromagnetic radiation having the first excitation wavelength and with electromagnetic radiation having a second excitation wavelength, wherein the second excitation wavelength is substantially equal to an absorption wavelength of the analyte, and wherein the analyzing comprises comparing the spectra emitted in response to the first excitation wavelength in the presence and in the absence of the second excitation wavelength.

4. The method of claim 3, wherein the Raman spectra analyzed comprise Stokes and anti-Stokes spectra.

5. The method of claim 3, wherein the concentration of analyte is determined in accordance with the following relationship:

space="preserve" listing-type="equation">C.sub.A =Δ

T/(C.sub.P I.sub.A ε

.sub.A Δ

t);

wherein C_A is the concentration of the analyte;

wherein Δ

T is the temperature shift between the temperature, in Kelvin, associated with Raman scattering emitted by the temperature probe in response to the first and second excitation wavelengths, and the temperature associated with Raman scattering emitted by the temperature probe in response to the first excitation wavelength in the absence of the second excitation wavelength;

wherein C_P is the heat capacity of the tissue;

wherein I_A is the intensity of the electromagnetic radiation of the second excitation wavelength;

wherein ε

_A is the absorption coefficient for a molecule of the analyte;

and wherein Δ

t is the duration of contact with the second excitation wavelength.

6. The method of claim 1, wherein the analyzing comprises measuring the Raman spectra associated with the analyte.

7. The method of claim 6, wherein the Raman spectra analyzed comprise anti-Stokes spectra.

8. The method of claim 1, wherein steps (a)-(c) are performed while the tissue is replete with blood and while the tissue is depleted of blood, and wherein the analyzing comprises determining the difference between the Raman spectra collected in the blood replete and blood depleted states.

9. The method of claim 1, wherein the tissue is blood.

10. The method of claim 1 further comprising the step of determining blood volume.

11. The method of claim 1, wherein the first excitation wavelength is about 647 to about 400 nm.

12. The method of claim 1, wherein the first excitation wavelength is about 550 to about 400 nm.

13. The method of claim 1, wherein the first excitation wavelength has a bandwidth of about 0.03 nm to about 0.000003 nm.

14. The method of claim 1, wherein the temperature probe is hemoglobin.

15. The method of claim 1, wherein the analyte is glucose.

16. The method of claim 1, wherein the analyte is creatinine, pyruvate or urea.

17. A method of measuring blood glucose in a subject comprising:

(a) contacting tissue of the subject with electromagnetic radiation having a first excitation wavelength, wherein the first excitation wavelength is about 550 to about 400 nm, and wherein the tissue of the subject is in a blood replete state;

(b) collecting Raman spectra emitted by the tissue in response to the first excitation wavelength, wherein the Raman spectra comprise Stokes and anti-Stokes spectra;

(c) analyzing the spectra collected in step (b) to determine the spectra associated with hemoglobin;

(d) contacting tissue of the subject with electromagnetic radiation having a second excitation wavelength, wherein the second excitation wavelength is about 9 to about 11 μ

m, and wherein the tissue of the subject is in a blood replete state;

(e) collecting Raman spectra emitted by the tissue in response to the first and second excitation wavelengths, wherein the Raman spectra comprise Stokes and anti-Stokes spectra;

(f) analyzing the spectra collected in step (e) to determine the spectra associated with hemoglobin;

(g) repeating steps (a)-(f) while the tissue is in a blood depleted state;

(h) determining net spectra emitted in response to the first and second excitation wavelengths, wherein the net spectra comprise the difference between the spectra obtained in the blood replete state and the blood depleted state;

(i) determining the temperature shift between the temperature, in Kelvin, associated with Raman scattering emitted by hemoglobin in response to the first and second excitation wavelengths, and the temperature associated with Raman scattering emitted by hemoglobin in response to the first excitation wavelength in the absence of the second excitation wavelength; and

(j) determining the concentration of glucose from the temperature shift determined in step (i).

18. The method of claim 17, wherein the concentration of glucose is determined in accordance with the following relationship:

space="preserve" listing-type="equation">C.sub.G =Δ

T/(C.sub.P I.sub.G ε

.sub.G Δ

t);

wherein C_G is the concentration of glucose;

wherein Δ

T is the temperature shift between the temperature, in Kelvin, associated with Raman scattering emitted by hemoglobin in response to the first and second excitation wavelengths, and the temperature associated with Raman scattering emitted by hemoglobin in response to the first excitation wavelength in the absence of the second excitation wavelength;

wherein C_P is the heat capacity of the tissue;

wherein I_G is the intensity of the electromagnetic radiation of the second excitation wavelength;

wherein ε

_G is the absorption coefficient for a molecule of glucose;

and wherein Δ

t is the duration of contact with the second excitation wavelength.

19. A method of measuring blood glucose in a subject comprising:

(a) contacting tissue of the subject with electromagnetic radiation having a first excitation wavelength, wherein the first excitation wavelength is about 550 to about 400 nm, and wherein the tissue of the subject is in a blood replete state;

(b) collecting Raman spectra emitted by the tissue, wherein the Raman spectra comprise anti-Stokes spectra;

(c) analyzing the collected spectra to determine the spectra associated with glucose;

(d) repeating steps (a)-(c) while the tissue is in a blood depleted state; and

(e) determining net spectra emitted in response to the first excitation wavelength, wherein the net spectra comprise the difference between the spectra obtained in the blood replete state and the blood depleted state, to obtain a value representative of the concentration of glucose.

20. An apparatus for measuring an analyte in a tissue in a subject comprising:

(a) a first light source that emits light having a first excitation wavelength that is substantially equal to an absorption wavelength of a temperature probe within the tissue;

(b) a second light source that emits light having a second excitation wavelength that is substantially equal to an absorption wavelength of the analyte;

(c) a detector that is disposed to receive Raman spectra scattered by the tissue in response to irradiation with the first and second excitation wavelengths and that produces output signals representative of the scattered Raman spectra; and

(d) a computer coupled to receive the output signals produced by the detector that processes the output signals to derive a value indicative of the concentration of the analyte in the tissue from a comparison of output signals representative of the Raman spectra scattered in response to the first and second excitation wavelengths.

21. The apparatus of claim 20, wherein the tissue is blood.

22. The apparatus of claim 20, wherein the temperature probe is hemoglobin.

23. The apparatus of claim 20, wherein the analyte is glucose.

24. The apparatus of claim 20, wherein the first excitation wavelength is about 550 to about 400 nm.

25. The apparatus of claim 20, wherein the second excitation wavelength is about 0.98, about 1.42, about 1.89, about 2.15, or about 9 to about 11 μ

m.

26. The apparatus of claim 20, wherein the detector comprises a wavelength selection spectrograph and a charge coupled device array.

27. The apparatus of claim 20, wherein the computer processes the output signals in accordance with the following relationship:

space="preserve" listing-type="equation">C.sub.A =Δ

T/(C.sub.P I.sub.A ε

.sub.A Δ

t);

wherein C_A is the concentration of the analyte;

wherein Δ

T is the temperature shift between the temperature, in Kelvin, associated with Raman scattering emitted by the temperature probe in response to the first and second excitation wavelengths, and the temperature associated with Raman scattering emitted by the temperature probe in response to the first excitation wavelength in the absence of the second excitation wavelength;

wherein C_P is the heat capacity of the tissue;

wherein I_A is the intensity of the electromagnetic radiation of the second excitation wavelength;

wherein ε

_A is the absorption coefficient for a molecule of the analyte;

and wherein Δ

t is the duration of contact with the second excitation wavelength.