Determination of a Measure of a Glycation End-Product or Disease State Using Tissue Fluorescence Lifetime

Abstract

The present invention provides methods and apparatuses for determining a measure of a tissue state in an individual. Light emitted by tissue of the individual due to fluorescence of a chemical with the tissue detected. The invention can comprise measuring the fluorescence lifetime in either time-domain or frequency domain modes. The invention can also comprise a variety of models relating fluorescence to a measure of tissue state, for example, multivariate models can be developed that relate lifetime trends of one or more constituents to increasing propensity to diabetes and pre-diabetes. Other biologic information can be used in combination with the fluorescence properties to aid in the determination of a measure of tissue state.

1 . A method of determining a tissue state of the tissue of an individual, where “tissue state” is any of (i) a disease state based on long-term changes (greater than one month duration) in tissue, (ii) a measure of chemical change based on long-term (greater than one month duration) glycemic control, (iii) a measure of glycation end-products in tissue, and (iv) a combination of the above, comprising: 
       (a) illuminating a portion of the tissue of the individual with excitation light; 
       (b) detecting light emitted from the tissue by fluorescence lifetime of a chemical within the tissue, where the tissue is not the lens of the eye; 
       (c) determining a first tissue reflectance characteristic at an excitation light wavelength, and a second tissue reflectance characteristic at a detection light wavelength; 
       (d) detecting light returned from the tissue at the detection wavelength in response to illumination at the excitation wavelength; 
       (e) determining a corrected fluorescence lifetime from the detected light and the first tissue reflectance characteristic and the second tissue reflectance characteristic; and 
       (f) determining the tissue state from the corrected fluorescence lifetime and a model relating fluorescence lifetime and tissue state. 
     
     
         2 . A method as in  claim 1 , wherein the excitation light has a wavelength in the range from 280 nm to 500 nm. 
     
     
         3 . A method as in  claim 2 , wherein the excitation light has a wavelength in the range from 315 nm to 500 nm. 
     
     
         4 . A method as in  claim 1 , wherein detecting light emitted from the tissue comprises detecting light at a wavelength between 280 nm and 850 nm. 
     
     
         5 . A method as in  claim 1 , wherein the fluorescence lifetime is measured in a time-domain mode. 
     
     
         6 . A method as in  claim 5 , wherein the time-domain mode measurement comprises illuminating the portion of the tissue with a short pulse of the excitation light and recording the time signature of the fluorescence decay of the chemical within the tissue. 
     
     
         7 . A method as in  claim 1 , wherein the fluorescence lifetime is measured in a frequency-domain mode. 
     
     
         8 . A method as in  claim 7 , wherein the frequency-domain mode measurement comprises illuminating the portion of the tissue with a modulation of the excitation light and recording the amplitude and phase shift of the fluorescence relative to the excitation modulation of the chemical within the tissue. 
     
     
         9 . A method as in  claim 1 , wherein detecting light comprises determining a relationship between a pulsed or modulated excitation light illumination and fluorescence lifetime at a detection wavelength, and wherein determining tissue state comprises comparing the relationship with a model defining a relationship between tissue state and relationships between the excitation light pulse or modulation and fluorescence lifetime at the detection wavelength. 
     
     
         10 . A method as in  claim 1 , further comprising acquiring biologic information relating to the individual, and wherein determining a tissue state comprises determining the tissue state from the information, the detected light, and a model relating biologic information, fluorescence lifetime and tissue state. 
     
     
         11 . A method as in  claim 1 , wherein the tissue comprises the skin of the individual. 
     
     
         12 . A method as in  claim 1 , wherein the model is determined according to: 
       (a) for each of a plurality of subjects: 
       (i) determining a fluorescence lifetime of a portion of the tissue of the subject; and 
       (ii) determining a tissue state of the subject; and 
       (b) applying a multivariate method to the plurality of fluorescence lifetime determinations and associated tissue state determinations to generate a model relating fluorescence lifetime to a tissue state. 
     
     
         13 . A method of determining a model relating fluorescence and tissue state, where “tissue state” is any of (i) a disease state based on long-term changes (greater than one month duration) in tissue, (ii) a measure of chemical change based on long-term (greater than one month duration) glycemic control, (iii) a measure of glycation end-products in tissue, and (iv) a combination of the above, comprising: 
       (a) for each of a plurality of subjects: 
       (i) determining a fluorescence lifetime of a portion of the tissue of the subject, where the tissue is not the lens of the eye, by detecting light emitted from the tissue by: 
       (1) determining a first tissue reflectance characteristic at an excitation light wavelength, and a second tissue reflectance characteristic at a detection light wavelength; 
       (2) detecting light returned from the tissue at the detection wavelength in response to illumination at the excitation wavelength; 
       (3) determining a corrected fluorescence lifetime from the detected light and the first tissue reflectance characteristic and the second tissue reflectance characteristic; 
       (ii) determining a tissue state of the subject; and 
       (b) applying a multivariate method to the plurality of corrected fluorescence lifetime determinations and associated tissue state determinations to generate a model relating corrected fluorescence lifetime to tissue state. 
     
     
         14 . A method as in  claim 13 , wherein determining a fluorescence lifetime of a portion of the tissue of the subject comprises: 
       a. Illuminating the portion of the tissue of the individual with pulsed or modulated excitation light; and 
       b. Detecting light emitted from the tissue by fluorescence lifetime of a chemical within the tissue. 
     
     
         15 . A method as in  claim 13 , wherein determining a tissue 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 previous disease state determination from disease state declared by the subject; 
       (e) determining a level of glycation endproducts in the tissue of the subject. 
     
     
         16 . A method as in  claim 13 , wherein applying a multivariate method comprises applying a multivariate model constructed according to the Partial Least Squares, Principal Components Regression, Principal Components Analysis, Classical Least Squares, Multiple Linear Regression, Ridge Regression algorithms, Linear Discriminant algorithms, Quadratic Discriminant algorithms, Logistic Regression algorithms, or a combination thereof. 
     
     
         17 . A method as in  claim 13  wherein the portion of the tissue comprises the skin of the subject. 
     
     
         18 . An apparatus for the determination of a tissue state in an individual, where “tissue state” is any of (i) a disease state based on long-term changes (greater than one month duration) in tissue, (ii) a measure of chemical change based on long-term (greater than one month duration) glycemic control, (iii) a measure of glycation end-products in tissue, and 
       (iv) a combination of the above, comprising: 
       (a) an illumination subsystem; 
       (b) a detection subsystem; and 
       (c) a control system, configured to use the illumination subsystem and the detection subsystem to determine a first tissue reflectance characteristic at an excitation light wavelength, and a second tissue reflectance characteristic at a detection light wavelength; and configured to use the illumination subsystem and detection subsystem to detect light returned from the tissue at the detection wavelength in response to illumination at the excitation wavelength 
       (d) an analysis subsystem, configured to determine a corrected fluorescence lifetime from the detected light and the first tissue reflectance characteristic and the second tissue reflectance characteristic, and comprising a model relating fluorescence lifetime of the skin of an individual to tissue state. 
     
     
         19 . An apparatus as in  claim 18 , further comprising an input subsystem configured to acquire biologic information comprising one of more of: gender of the individual, weight of the individual, waist circumference of the individual, history of disease of the individual's family, ethnicity, skin melanin content, smoking history of the individual, or a combination thereof; and 
       wherein the model relates fluorescence lifetime of the skin of an individual and biologic information to tissue state. 
     
     
         20 . An apparatus as in  claim 18 , wherein the illumination subsystem comprises means for illuminating with a short pulse of the excitation light source and the detection subsystem comprises means for measuring the fluorescence lifetime by recording the time signature of the fluorescence decay.