Tissue modulation process for quantitative noninvasive in vivo spectroscopic analysis of tissues

• US 6,289,230 B1
• Filed: 07/07/1999
• Issued: 09/11/2001
• Est. Priority Date: 07/07/1998
• 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:
  US09/349,061
• Time in Patent Office: 797 Days
• Field of Search: 600/310, 600/317, 600/322, 600/323, 600/326, 600/330, 600/335, 600/336, 600/476, 600/316
• US Class Current: 600/322
• CPC Class Codes: A61B 5/0048 Detecting, measuring or recording by applying mechanical forces or stimuli A61B5/021, A61B5/4884 and A61B9/00 take precedence
• 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 2021/655 Stimulated Raman
• CPC Class Codes: G01N 21/6486 Measuring fluorescence of biological material, e.g. DNA, RNA, cells G01N21/6428 takes precedence
• CPC Class Codes: G01N 21/65 Raman scattering

Abstract

Methods are provided for noninvasively measuring blood volume and analyte concentration and for obtaining spectroscopic information relating to immobile tissues, such as skin. One method is for determining concentration of an analyte, such as glucose, in blood of a subject. The method comprises irradiating a region of tissue, such as a fingertip, of the subject with a light source; collecting fluorescence spectra emitted by the region of tissue, the quantity of fluorescence spectra being indicative of blood volume; and collecting Raman spectra emitted by the region of tissue at a wavelength range that corresponds to the analyte. The method further comprises dividing the collected Raman spectra by the collected fluorescence spectra to obtain a number proportional to the concentration of analyte per unit blood volume. The method can further comprise determining the integral of net collected spectra, net collected spectra being a difference between spectra collected while the region of tissue is in a blood-replete state and spectra collected while the region of tissue is in a blood-depleted state. The method can further comprise enhancing the spectra collected by performing adjacent averaging smoothing operations. Blood volume in a region of tissue for spectroscopic measurement can be modulated by applying an ultrasonic transducer to the region of tissue, and also be applying a tourniquet.

Claims

1. A noninvasive method of determining concentration of an analyte in blood of a subject comprising:

a) irradiating a region of tissue of the subject with a light source;

b) collecting fluorescence spectra emitted by the region of tissue, the quantity of fluorescence spectra being indicative of blood volume;

c) collecting Raman spectra emitted by the region of tissue at a wavelength range that corresponds to the analyte, the quantity of Raman spectra being indicative of the amount of analyte; and

d) dividing the collected Raman spectra by the collected fluorescence spectra to obtain a number proportional to the concentration of analyte per unit blood volume.

2. The method of claim 1, wherein the fluorescence and Raman spectra are collected while the region of tissue is in a blood-replete state and collected while the region of tissue is in a blood-depleted state, and wherein the method further comprises determining the integral of net collected spectra, net collected spectra being a difference between spectra collected while the region of tissue is in a blood-replete state and spectra collected while the region of tissue is in a blood-depleted state, wherein the dividing of step (d) is performed by dividing the integral of the net collected Raman spectra at the wavelength range corresponding to the analyte by the integral of the net collected fluorescence spectra.

3. The method of claim 2, wherein the net collected Raman spectra is determined by:

4. The method of claim 2, further comprising enhancing the spectra collected by:

i) performing a 61-501 point adjacent averaging smoothing operation on the net collected spectra;

ii) subtracting the smoothed spectra from the net collected spectra; and

iii) performing a 3-27 point adjacent averaging smoothing operation on the result of step (ii).

5. The method of claim 4, wherein the adjacent averaging smoothing operation of step (i) is a 85-201 point smoothing operation.

6. The method of claim 5, wherein the adjacent averaging smoothing operation of step (i) is a 101 point smoothing operation.

7. The method of claim 4, wherein the adjacent averaging smoothing operation of step (iii) is a 7 point smoothing operation.

8. The method of claim 2, wherein the blood-depleted state is achieved by applying a tourniquet to the tissue or by pressing the tissue against a surface.

9. The method of claim 2, wherein the blood-replete and blood-depleted states are achieved by applying an ultrasonic transducer to the region of tissue.

10. The method of claim 1, wherein the light source emits light having a wavelength of about 785 nm to about 850 nm.

11. The method of claim 10, wherein the wavelength is about 785 nm.

12. The method of claim 10, wherein the wavelength is about 805 or about 808 nm.

13. The method of claim 1, wherein the light source is a laser.

14. The method of claim 1, wherein the analyte is glucose, urea, creatinine, total protein, free fatty acids, monoglycerides, diglycerides, triglycerides, creatinine, alpha helix exposed exchangeable protein associated amide protons, cholesterol, pyruvate, tyrosine, tryptophan, bicarbonate, electrolytes, lactic acid, a drug, O₂, CO₂ or NO.

15. The method of claim 1, wherein the region of tissue is a fingertip.

16. A noninvasive method of determining concentration of an analyte in blood of a subject comprising:

a) irradiating a region of tissue of the subject with a light source;

b) collecting Raman spectra emitted by the region of tissue at a wavelength range that corresponds to the analyte, the quantity of Raman spectra being indicative of the amount of analyte; and

c) measuring absorption of incident light by the region of tissue, the amount of absorbed light being indicative of blood volume;

d) dividing the collected Raman spectra by the amount of absorbed incident light to obtain the concentration of analyte per unit blood volume.

17. The method of claim 16, wherein the collecting of step (b) and the measuring of step (c) are performed while the region of tissue is in a blood-replete state and while the region no of tissue is in a blood-depleted state, and wherein the dividing of step (d) is performed by dividing the net collected Raman spectra by the net absorbed light, wherein net refers to the difference between the blood-replete and blood-depleted states.

18. The method of claim 17, further comprising enhancing the spectra collected by:

i) performing a 61-501 point adjacent averaging smoothing operation on the net collected spectra;

ii) subtracting the smoothed spectra from the net collected spectra; and

iii) performing a 3-27 point adjacent averaging smoothing operation on the result of step (ii).

19. The method of claim 18, wherein the adjacent averaging smoothing operation of step (i) is a 85-201 point smoothing operation.

20. The method of claim 19, wherein the adjacent averaging smoothing operation of step (i) is a 101 point smoothing operation.

21. The method of claim 18, wherein the adjacent averaging smoothing operation of step (iii) is a 7 point smoothing operation.

22. The method of claim 17, wherein the blood-depleted state is achieved by applying a tourniquet to the tissue or by pressing the tissue against a surface.

23. The method of claim 17, wherein the blood-replete and blood-depleted states are achieved by applying an ultrasonic transducer to the region of tissue.

24. The method of claim 16, wherein the light source emits light having a wavelength of about 785 nm to about 850 nm.

25. The method of claim 24, wherein the wavelength is about 785 nm.

26. The method of claim 24, wherein the wavelength is about 805 or about 808 nm.

27. The method of claim 16, wherein the light source is a laser.

28. The method of claim 16, further comprising irradiating the tissue with a second light source having a wavelength that corresponds to an isosbestic point for oxy-deoxyhemoglobin.

29. The method of claim 28, wherein the second light source is a laser, a black body source or a light emitting diode.

31. The method of claim 16, wherein the analyte is glucose, urea, creatinine, total protein, free fatty acids, monoglycerides, diglycerides, triglycerides, creatinine, alpha helix exposed exchangeable protein associated amide protons, cholesterol, pyruvate, tyrosine, tryptophan, bicarbonate, electrolytes, lactic acid, a drug, O₂, CO₂ or NO.

32. The method of claim 16, wherein the region of tissue is a fingertip.

30. The method of claim 30, wherein the light source of step (a) has a wavelength of about 785 nm and the second light source has a wavelength of about 805 or about 808 nm.