Determination of disease state using raman spectroscopy of tissue

• US 7,725,144 B2
• Filed: 12/19/2003
• Issued: 05/25/2010
• Est. Priority Date: 04/04/2002
• Status: Expired due to Fees

• Current Assignee: Veralight, Inc. (Britannia Life Sciences, Inc.)
• Original Assignee: Veralight, Inc. (Britannia Life Sciences, Inc.)
• Inventors: Ediger, Marwood Neal, Gardner, Craig M., Hull, Edward L.
• Primary Examiner(s): Casler; Brian
• Assistant Examiner(s): Lamprecht; Joel M
• Application Number:
  US10/742,110
• Publication Number:
  US 20050090750A1
• Time in Patent Office: 2,349 Days
• Field of Search: 600/476, 600/477, 600/473, 600/310, 600/475, 600/431, 600/342, 424/9.1, 398/79, 356/301
• US Class Current: 600/310
• 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 5/0064 Body surface scanning
• CPC Class Codes: A61B 5/0066 Optical coherence imaging
• CPC Class Codes: A61B 5/0068 Confocal scanning
• CPC Class Codes: A61B 5/0071 by measuring fluorescence emission
• CPC Class Codes: A61B 5/0075 by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy A61B5/0071 takes precedence
• CPC Class Codes: A61B 5/061 Determining position of a probe within the body employing means separate from the probe, e.g. sensing internal probe position employing impedance electrodes on the surface of the body A61B1/00158 takes precedence
• CPC Class Codes: A61B 5/412 Detecting or monitoring sepsis
• CPC Class Codes: A61B 5/441 Skin evaluation, e.g. for skin disorder diagnosis
• CPC Class Codes: A61B 5/443 Evaluating skin constituents, e.g. elastin, melanin, water

Abstract

A method of determining disease state in an individual. A portion of the tissue of the individual is illuminated with excitation light, then light emitted by the tissue due to Raman scattering of a chemical with the tissue responsive to the excitation light is detected. The detected light can be combined with a model relating Raman emission with disease state to determine a disease state of the individual. The invention can comprise single wavelength excitation light, scanning of excitation light (illuminating the tissue at a plurality of wavelengths), detection at a single wavelength, scanning of detection wavelengths (detecting emitted light at a plurality of wavelengths), and combinations thereof. The invention also can comprise correction techniques that reduce determination errors due to detection of light other than that from Raman emission of a chemical in the tissue. For example, the reflectance of the tissue can lead to errors if appropriate correction is not employed. The invention can also comprise a variety of models relating Raman emission to disease state, including a variety of methods for generating such models. Other biologic information can be used in combination with the Raman spectral properties to aid in the determination of disease state. The invention also comprises apparatuses suitable for carrying out the method, including appropriate light sources, detectors, and models (for example, implemented on computers) used to relate detected Raman emission and disease state.

Claims

1. A method of determining a disease state in an individual, where “

determining a disease state”

comprises determining the presence or likelihood of diabetes;

the degree of progression of diabetes;

a change in the presence, likelihood, or progression of diabetes;

a probability of having, not having, developing, or not developing diabetes;

the presence, absence, progression, or likelihood of complications from diabetes, and where “

determining a disease state”

does not comprise measurement of glucose concentration, the method comprising;

a. illuminating a portion of the tissue of the individual with excitation light;

b. detecting light emitted from the tissue by Raman scattering of a chemical within the tissue;

c. acquiring biologic information relating to the individual; and

d. determining the disease state from the information, the detected light, and a model relating biologic information, Raman scattering and disease state.

2. A method as in claim 1, wherein the excitation light has a first wavelength at a first time, and a second wavelength, different from the first wavelength, at a second time.

3. A method as in claim 1, wherein detecting light emitted from the tissue comprises detecting light at each of a plurality of wavelengths.

4. A method as in claim 3, wherein the excitation light has a single wavelength, and wherein detecting light emitted from the tissue comprises detecting light at a plurality of wavelengths.

5. A method as in claim 1, wherein detecting light emitted from the tissue comprises:

a. determining a tissue reflectance characteristic at an excitation light wavelength;

b. detecting light returned from the tissue in response to illumination at the excitation wavelength;

c. determining a corrected Raman measurement from the detected light and the tissue reflectance characteristic;

d. and wherein determining the disease state comprises determining the disease state from the corrected Raman measurement and a model relating Raman scattering and disease state.

6. A method as in claim 1, wherein detecting light emitted from the tissue comprises:

a. determining a tissue reflectance characteristic at a detection wavelength;

b. detecting light at the detection wavelength returned from the tissue in response to illumination;

c. determining a corrected Raman measurement from the detected light and the tissue reflectance characteristic;

d. and wherein determining the disease state comprises determining the disease state from the corrected Raman measurement and a model relating Raman scattering and disease state.

7. A method as in claim 1, wherein detecting light emitted from the tissue comprises:

a. determining a first tissue reflectance characteristic at an excitation light wavelength;

b. determining a second tissue reflectance characteristic at a detection wavelength;

c. detecting light at the detection wavelength returned from the skin in response to illumination at the excitation wavelength;

d. determining a corrected Raman measurement from the detected light and the first and second tissue reflectance characteristics;

e. and wherein determining the disease state comprises determining the disease state from the corrected Raman measurement and a model relating Raman scattering and disease state.

8. A method as in claim 5, wherein determining a tissue reflectance characteristic comprises:

a. illuminating the tissue with reflectance illumination light having an excitation wavelength;

b. detecting reflectance light having the excitation wavelength reflected from the skin, using the same detector as used to detect light returned from the tissue; and

c. establishing a tissue reflectance characteristic from a relationship between the reflectance illumination light and the reflectance light.

9. A method as in claim 5, wherein determining a tissue reflectance characteristic comprises:

a. illuminating the portion of the tissue with reflectance illumination light having an excitation wavelength;

b. detecting reflectance light having the excitation wavelength reflected from the portion of the skin; and

c. establishing a tissue reflectance characteristic from a relationship between the reflectance illumination light and the reflectance light.

10. A method as in claim 6, wherein determining a tissue reflectance characteristic comprises:

a. illuminating the tissue with reflectance illumination light having a wavelength the same as the detection wavelength;

b. detecting reflectance light having the detection wavelength reflected from the skin, using the same detector as used to detect light returned from the tissue; and

c. establishing a tissue reflectance characteristic from a relationship between the reflectance illumination light and the reflectance light.

11. A method as in claim 6, wherein determining a tissue reflectance characteristic comprises:

a. illuminating the portion of the tissue with reflectance illumination light having a wavelength the same as the detection wavelength;

b. detecting reflectance light having the detection wavelength reflected from the portion of the skin; and

c. establishing a tissue reflectance characteristic from a relationship between the reflectance illumination light and the reflectance light.

12. A method as in claim 1, wherein detecting light comprises determining a relationship between an excitation wavelength and Raman emission at a detection wavelength, and wherein determining disease state comprises comparing the relationship with a model defining a relationship between disease state and relationships between the excitation wavelength and Raman emission at the detection wavelength.

13. A method as in claim 12, wherein detecting light comprises determining a relationship between illumination at an excitation wavelength and Raman emission at a plurality of detection wavelengths, and wherein determining disease state comprises comparing the relationship with a model defining a relationship between disease state and relationships between the excitation wavelength and Raman emission at the plurality of detection wavelengths.

14. A method as in claim 12, wherein detecting light comprises determining a relationship between illumination at a plurality of excitation wavelengths and Raman emission at a plurality of detection wavelengths, and wherein determining disease state comprises comparing the relationship with a model defining a relationship between disease state and relationships between the plurality of excitation wavelengths and Raman emission at the plurality of detection wavelength.

15. A method as in claim 1, wherein the biologic information comprises age of the individual, height of the individual, weight of the individual, history of disease in the individual'"'"'s family, ethnicity, skin melanin content, laser-Doppler information from the subject'"'"'s tissue, or a combination thereof.

16. A method as in claim 1, wherein the tissue comprises the skin of the individual.

17. A method as in claim 1, wherein the model is determined according to:

a. for each of a plurality of subjects;

i. determining a Raman emission property of a portion of the tissue of the subject;

ii. determining a disease state of the subject;

b. applying a multivariate method to the plurality of Raman emission property determinations and associated disease state determinations to generate a model relating Raman emission property to disease state.

39. A method as in claim 1, wherein the tissue comprises the dermis of the individual.

18. A method of determining a disease state in an individual, where “

determining a disease state”

comprises determining the presence or likelihood of diabetes;

the degree of progression of diabetes;

a change in the presence, likelihood, or progression of diabetes;

a probability of having, not having, developing, or not developing diabetes;

the presence, absence, progression, or likelihood of complications from diabetes, and where “

determining a disease state”

does not comprise measurement of glucose concentration, the method comprising;

a. establishing an interface between a optical system and a portion of the skin of the individual;

b. determining a relationship of illumination light at an excitation wavelength and the response of the skin at a detection wavelength for each of a plurality of pairings of excitation wavelength and detection wavelength;

c. determining a tissue reflectance property of the skin at each of the illumination wavelengths and at each of the detection wavelengths;

d. determining a measure of the intrinsic Raman emission of the skin from the relationships of illumination light and detected light and the tissue reflectance properties;

e. acquiring biologic information relating to the subject; and

f. determining the disease state of the individual from the information, the intrinsic Raman emission, and a model relating intrinsic biologic information, Raman emission and disease state.

19. A method as in claim 18, wherein the biologic information comprises information from fluorescence spectroscopic investigation of the subject.

20. A method as in claim 18, wherein the biologic information comprises age of the subject, height of the subject, weight of the subject, history of disease in the subject'"'"'s family, ethnicity, skin melanin content, blood HDL cholesterol level of the subject, blood LDL cholesterol level of the subject, blood triglycerides level of the subject, or a combination thereof.

21. A method of determining a model relating biologic information, Raman emission and disease state, where “

disease state”

comprises the presence or likelihood of diabetes;

the degree of progression of diabetes;

a change in the presence, likelihood, or progression of diabetes;

a probability of having, not having, developing, or not developing diabetes;

the presence, absence, progression, or likelihood of complications from diabetes, and where “

determining a disease state”

does not comprise measurement of glucose concentration, the method comprising;

a. for each of a plurality of subjects;

i. determining a Raman emission property of a portion of the tissue of the subject;

ii. acquiring biologic information from the subject;

iii. determining a disease state of the subject;

b. applying a multivariate method to the plurality of Raman emission property determinations, biologic information acquisitions, and associated disease state determinations to generate a model relating biologic information and Raman emission property to disease state.

22. A method as in claim 21, wherein determining a Raman emission property comprises determining an intrinsic Raman emission of the portion of the tissue.

23. A method as in claim 21, wherein determining a Raman emission property comprises determining an intrinsic Raman emission of the portion of the tissue at each of a plurality of detection wavelengths responsive to excitation light having an excitation wavelength.

24. A method as in claim 21, wherein determining a Raman emission property comprises determining an intrinsic Raman emission of the portion of the tissue at pairings of a plurality of detection wavelengths and a plurality of excitation wavelengths.

25. A method as in claim 21, wherein determining a Raman emission property of a portion of the tissue of the subject comprises:

a. illuminating the portion of the tissue of the individual with excitation light;

b. detecting light emitted from the tissue by Raman emission of a chemical within the tissue;

26. A method as in claim 25, wherein detecting light emitted from the tissue comprises:

a. determining a tissue reflectance characteristic at an excitation light wavelength;

b. detecting light returned from the tissue in response to illumination at the excitation wavelength;

c. determining a corrected Raman emission measurement from the detected light and the tissue reflectance characteristic.

27. A method as in claim 25, wherein detecting light emitted from the tissue comprises:

a. determining a tissue reflectance characteristic at a detection wavelength;

b. detecting light at the detection wavelength returned from the tissue in response to illumination;

c. determining a corrected Raman emission measurement from the detected light and the tissue reflectance characteristic.

28. A method as in claim 25, wherein detecting light emitted from the tissue comprises:

a. determining a first tissue reflectance characteristic at an excitation light wavelength;

b. determining a second tissue reflectance characteristic at a detection wavelength;

c. detecting light at the detection wavelength returned from the skin in response to illumination at the excitation wavelength;

d. determining a corrected Raman emission measurement from the detected light and the first and second tissue reflectance characteristics.

29. A method as in claim 21, wherein determining the disease state comprises at least one of:

a. evaluating the subject according to an OGTT;

b. evaluating the subject according to an FPG;

c. evaluating the subject according to an HbA1c test;

d. determining a level of glycation endproducts in the tissue of the subject.

30. A method as in claim 21, wherein the tissue is not the eye, and wherein applying a multivariate method comprises applying a multivariate model constructed using ordinary least-squares(OLS), Partial Least Squares (PLS), Principal Components Regression (PCR), a Tikhonov-regularized least-squares model, or a combination thereof.

31. A method as in claim 21, wherein the portion of the tissue comprises the skin of the subject.

40. A method as in claim 21, wherein the tissue is not the eye, and wherein applying a multivariate method comprises applying a multivariate model constructed using a nonlinear technique.

32. An apparatus for the determination of disease state in an individual, where “

disease state”

comprises the presence or likelihood of diabetes;

the degree of progression of diabetes;

a change in the presence, likelihood, or progression of diabetes;

a probability of having, not having, developing, or not developing diabetes;

the presence, absence, progression, or likelihood of complications from diabetes, and where “

determining a disease state”

does not comprise measurement of glucose concentration, the apparatus comprising;

a. an illumination subsystem;

b. a detection subsystem;

c. an analysis subsystem, comprising a model relating biologic information and Raman emission property of the skin of an individual to disease state.

33. An apparatus as in claim 32, wherein the model is determined according to:

a. for one or more of a plurality of subjects;

i. determining a Raman emission property of a portion of the tissue of the subject and acquiring biologic information concerning the subject;

ii. determining a disease state of the subject, where “

disease state”

comprises the presence or likelihood of diabetes;

the degree of progression of diabetes;

a change in the presence, likelihood, or progression of diabetes;

a probability of having, not having, developing, or not developing diabetes;

the presence, absence, progression, or likelihood of complications from diabetes;

b. applying a multivariate method to the plurality of biologic information acquisitions and Raman emission property determinations and associated disease state determinations to generate a model relating Raman emission property to disease state.

34. A method of determining disease state in an individual, where “

determining a disease state”

comprises determining the presence or likelihood of diabetes;

the degree of progression of diabetes;

a change in the presence, likelihood, or progression of diabetes;

a probability of having, not having, developing, or not developing diabetes;

the presence, absence, progression, or likelihood of complications from diabetes, and where “

determining a disease state”

does not comprise measurement of glucose concentration, the method comprising;

a. determining a Raman emission property of a portion of the skin of the individual and biologic information concerning the individual;

b. using a multivariate method to determine a disease state of the individual from the Raman emission property and the biologic information.

35. A method according to claim 34, wherein:

a. the Raman emission property comprises the intrinsic Raman emission of the portion of the skin;

b. the disease state comprises the presence of diabetes;

c. using a multivariate method comprises applying a multivariate model relating intrinsic Raman emission of skin and biologic information to disease state.

36. A method according to claim 34, wherein determining a Raman emission property comprises determining the tissue'"'"'s response to amplitude-modulated excitation light, a short pulse of excitation light, or polarized excitation light, or a combination thereof.

37. A method according to claim 34, wherein determining a Raman emission property comprises the using confocal detection or optical coherence tomography to discriminate the tissue depth from which the Raman emission property originates.

38. A method according to claim 34, wherein determining a Raman emission property comprises using raster scanning or imaging optics to obtain information regarding the spatial distribution of the Raman emission property.