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

Abstract

A method of determining a measure of a tissue state (e.g., glycation end-product or 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 fluorescence of a chemical with the tissue responsive to the excitation light is detected. The detected light can be combined with a model relating fluorescence with a measure of tissue state to determine a tissue state. The invention can comprise various light excitation and detection configurations. The invention also can comprise correction techniques that reduce determination errors due to detection of light other than that from fluorescence of a chemical in the tissue. Other biologic information can be used in combination with the fluorescence properties to aid in the determination of a measure of tissue state. The invention also comprises apparatuses suitable for carrying out the method.

What we claim is: 
     
         1 . A method of determining a tissue state of the tissue of an individual, where “tissue state” comprises any of (i) presence or likelihood of diabetes; the degree of progression of diabetes; (ii) a change in the presence, likelihood, or progression of diabetes; (iii) a probability of having, not having, developing, or not developing diabetes; (iv) the presence, absence, progression, or likelihood of complications from diabetes, in each case based on long-term changes (greater than one month duration) in tissue comprising determining a measure of fluorescence response of at least a portion of the tissue, other than the lens of the eye, of the individual to excitation light, and determining the tissue state from the measure of fluorescence response. 
     
     
         2 . A method as in  claim 1 , wherein the excitation light comprises light with nonzero intensity at a wavelength in the range from 280 nm to 850 nm. 
     
     
         3 . 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. 
     
     
         4 . A method as in  claim 1 , wherein determining a measure of fluorescence response comprises subjecting the tissue to light having nonzero intensity at an excitation wavelength, and measuring light emitted from the tissue at one or more detection wavelengths greater than the excitation wavelength. 
     
     
         5 . A method as in  claim 1 , wherein determining a measure of fluorescence response comprises subjecting the tissue to light having nonzero intensity at an excitation wavelength, and measuring light emitted from the tissue at a plurality of detection wavelengths greater than the excitation wavelength. 
     
     
         6 . A method as in  claim 1 , wherein determining a measure of fluorescence response comprises subjecting the tissue to light having nonzero intensity at a plurality of excitation wavelengths, and measuring light emitted from the tissue at one or more detection wavelengths greater than the excitation wavelength. 
     
     
         7 . A method as in  claim 1 , wherein determining the tissue state from the measure of fluorescence response comprises using a model relating fluorescence response to tissue state. 
     
     
         8 . 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 fluorescence response and the biologic information. 
     
     
         9 . A method as in  claim 1 , wherein the tissue comprises the skin of the individual. 
     
     
         10 . A method according to  claim 1 , wherein determining a fluorescence 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. 
     
     
         11 . A method according to  claim 1 , wherein the tissue state comprises the presence of glycation end-products, the concentration of glycation end-products, the change in the concentration of glycation end-products, the presence of glycated collagen, the concentration of glycated collagen, the change in the concentration of glycated collagen, the disease state of the individual, or a combination thereof. 
     
     
         12 . A method according to  claim 1 , wherein determining a fluorescence property comprises using confocal detection or optical coherence tomography to discriminate the tissue depth from which the fluorescence property originates. 
     
     
         13 . An apparatus for the determination of a tissue state in an individual, where “tissue state” comprises any of (i) presence or likelihood of diabetes; the degree of progression of diabetes; (ii) a change in the presence, likelihood, or progression of diabetes; (iii) a probability of having, not having, developing, or not developing diabetes; (iv) the presence, absence, progression, or likelihood of complications from diabetes, in each case based on long-term changes (greater than one month duration) in tissue, comprising:
 (a) a fluorescence measurement system, configured to measure a fluorescence response of tissue, other than the lens of the eye, of the individual to incident light; and 
 (b) an analysis system, configured to determine the tissue state of the individual from the measured fluorescence response. 
 
     
     
         14 . An apparatus as in  claim 13 , wherein the analysis system comprises a model relating fluorescence response to tissue state. 
     
     
         15 . An apparatus as in  claim 13 , wherein the model is determined according to:
 (a) for each of a plurality of subjects:   (i) determining a fluorescence property of a portion of the tissue of the subject;   (ii) determining a tissue state of the subject;   (b) applying a multivariate method to the plurality of fluorescence property determinations and associated tissue state determinations to generate a model relating fluorescence property to tissue state.   
     
     
         16 . An apparatus as in  claim 13 , wherein the fluorescence measurement system is configured to determine the tissue's response to amplitude-modulated excitation light, a short pulse of excitation light, or polarized excitation light, or a combination thereof. 
     
     
         17 . An apparatus as in  claim 13 , wherein the analysis system is configured to determine the tissue state from the measured fluorescence response and from biologic information relating to the individual. 
     
     
         18 . An apparatus as in  claim 17 , wherein the analysis system comprises a model relating a fluorescence response and biologic information to tissue state. 
     
     
         19 . An apparatus as in  claim 13 , wherein the fluorescence measurement system is configured to determine a fluorescence response of the tissue at a plurality of detection wavelengths. 
     
     
         20 . An apparatus as in  claim 13 , wherein the fluorescence measurement system is configured to determine a fluorescence response of the tissue to excitation light at a plurality of excitation wavelengths.