Non-invasive measurement of blood analytes using photodynamics

Abstract

The determination of blood glucose in an individual is carried out by projecting illuminating light into an eye of the individual to illuminate the retina with the light having wavelengths that are absorbed by rhodopsin and with the intensity of the light varying in a prescribed temporal manner. The light reflected from the retina is detected to provide a signal corresponding to the intensity of the detected light, and the detected light signal is analyzed to determine the changes in form from that of the illuminating light. For a biased sinusoidal illumination, these changes can be expressed in terms of harmonic content of the detected light. The changes in form of the detected light are related to the ability of rhodopsin to absorb light and regenerate, which in turn is related to the concentration of blood glucose, allowing a determination of the relative concentration of blood glucose. Other photoreactive analytes can similarly be determined by projecting time varying illuminating light into the eye, detecting the light reflected from the retina, and analyzing the detected light signal to determine changes in form of the signal due to changes in absorptivity of a photoreactive analyte.

1 - 28 . (canceled)  
   
   
       29 . A method for use in the determination of the blood glucose concentration in an individual, comprising: 
 (a) Non-invasively measuring the rate of a biochemical process of the body;    (b) Determining the blood glucose concentration from the measured rate.    
   
   
       30 . The method according to  claim 29  wherein the biochemical process comprises a photodynamic process.  
   
   
       31 . The method according to  claim 29  wherein the biochemical process comprises the reduction of all-trans-retinal to all-trans-retinol.  
   
   
       32 . The method according to  claim 29  wherein at least a portion of the biochemical process occurs in the eye.  
   
   
       33 . The method according to  claim 32  wherein the non-invasively measuring step occurs in the eye without dilation of the pupil.  
   
   
       34 . The method according to  claim 29  wherein the biochemical process comprises the production of rhodopsin.  
   
   
       35 . The method according to  claim 29  wherein the rhodopsin is cone rhodopsin.  
   
   
       36 . The method according to  claim 29  wherein the rhodopsin is rod rhodopsin.  
   
   
       37 . The method according to  claim 29  wherein the non-invasively measuring step comprises measuring a rate of change in the reflectance of a surface in the eye.  
   
   
       38 . The method according to  claim 37  wherein the surface of the eye comprises the retina.  
   
   
       39 . The method according to  claim 38  wherein the surface in the eye comprises mostly cones.  
   
   
       40 . The method according to  claim 38  wherein the surface in the eye comprises rods and cones.  
   
   
       41 . A method of determining the blood glucose concentration in an individual, comprising: 
 (a) non-invasively measuring a formation rate of a substance in the individual; and    (b) determining the blood glucose concentration in the individual from the measured formation rate of the substance.    
   
   
       42 . The method according to  claim 41  wherein the non-invasively measuring step is performed in the eye.  
   
   
       43 . The method according to  claim 41  wherein non-invasively measuring comprises measuring the rate of change of the reflectance of a portion of the eye.  
   
   
       44 . The method according to  claim 41  wherein non-invasively measuring comprises illuminating the eye.  
   
   
       45 . The method according to  claim 41  wherein illuminating the eye comprises illuminating the retina.  
   
   
       46 . The method according to  claim 45  wherein illuminating the eye comprises illuminating the eye with a wavelength of light absorbed by rod rhodopsin.  
   
   
       47 . The method according to  claim 45  wherein illuminating the eye comprises illuminating the eye with a wavelength of light absorbed by cone rhodopsin.  
   
   
       48 . The method according to  claim 41  wherein measuring comprises initiating a photodynamic process in the eye.  
   
   
       49 . The method according to  claim 41  wherein the substance comprises cone rhodopsin.  
   
   
       50 . The method according to  claim 41  wherein the substance comprises rod rhodopsin.  
   
   
       51 . A method for determining the blood glucose concentration of an individual, comprising: 
 (a) measuring a formation rate of visual pigment in an eye of the individual; and    (b) determining the blood glucose concentration of the individual from the measured formation rate of visual pigment.    
   
   
       52 . The method according to  claim 51  wherein measuring comprises non-invasively measuring.  
   
   
       53 . The method according to  claim 51  wherein measuring a formation rate comprises measuring the rate of change of the reflectance of a portion of the eye.  
   
   
       54 . The method according to  claim 51  wherein the measuring step comprises illuminating the retina.  
   
   
       55 . The method according to  claim 54  wherein the measuring step comprises illuminating the retina using an illumination source outside of the eye.  
   
   
       56 . The method according to  claim 51  wherein the measuring step comprises illuminating the fovea.  
   
   
       57 . The method according to  claim 54  wherein illuminating the eye comprises illuminating the eye with a wavelength of light absorbed by rod rhodopsin.  
   
   
       58 . The method according to  claim 54  wherein illuminating the eye comprises illuminating the eye with a wavelength of light absorbed by cone rhodopsin.  
   
   
       59 . The method according to  claim 54  or  56  wherein illuminating the eye initiates a photodynamic process in the eye.  
   
   
       60 . The method according to  claim 59  wherein the photodynamic process is a regenerative process.  
   
   
       61 . The method according to  claim 59  wherein the photodynamic process is a depletive process.  
   
   
       62 . The method according to  claim 60  wherein the product of the regenerative process is visual pigment.  
   
   
       63 . The method according to  claim 61  wherein the product of the regenerative process is visual pigment.  
   
   
       64 . The method according to  claim 54  wherein the measuring step comprises illuminating the eye with a periodically applied stimulus of light.  
   
   
       65 . The method according to  claim 54  wherein the measuring step comprises illuminating the eye without dilating the pupil.  
   
   
       66 . A method for determining the blood glucose concentration of an individual, comprising: 
 (a) Initiating a photodynamic process in the eye of a person;    (b) Measuring the glucose use rate of the photodynamic process; and    (c) Determining the blood glucose concentration of the person from the measured glucose use rate.    
   
   
       67 . The method according to  claim 66  wherein the initiating step is performed without dilating the pupil.  
   
   
       68 . The method according to  claim 66  the initiating step further comprising illuminating the eye with light.  
   
   
       69 . The method according to  claim 68  the initiating step further comprising illuminating the eye with light having a wavelength known to activate rhodopsin.  
   
   
       70 . The method according to  claim 69  the initiating step further comprising illuminating the eye with light having a wavelength known to activate rhodopsin in areas of the fovea.  
   
   
       71 . The method according to  claim 66  wherein the biochemical process comprises the reduction of all-trans-retinal to all-trans-retinol.  
   
   
       72 . The method according to  claim 66  wherein the photodynamic process causes a change in the reflectance of a portion of the eye.  
   
   
       73 . The method according to  claim 72  wherein the portion of the eye comprises the retina.  
   
   
       74 . The method according to  claim 73  wherein the portion of the eye comprises the fovea.  
   
   
       75 . The method according to  claim 69  wherein the portion of the eye comprises a portion of the fovea.  
   
   
       76 . The method according to  claim 72  wherein the portion of the eye comprises mostly cones.  
   
   
       77 . The method according to  claim 72  wherein the portion of the eye comprises both rods and cones.  
   
   
       78 . The method according to  claim 66  wherein the photodynamic process comprises the generation of NADPH.  
   
   
       79 . An apparatus for glucose measurements, comprising: 
 (a) An illuminating optics system adapted to provide illuminating light into the eye at a wavelength selected to initiate a photodynamic process in the eye;    (b) An optical detector configured to receive illuminating light reflected from the eye and output optical data relating to the photodynamic process; and    (c) An optical data analysis system configured to process the optical data to calculate the blood glucose level.    
   
   
       80 . The apparatus according to  claim 79  wherein the illuminating optics system provides illuminating light into the eye at a wavelength range matching the active range of rhodopsin molecules.  
   
   
       81 . The apparatus according to  claim 79  wherein the illuminating optics system provides a 5 to 30 degree conical view of the retina to be illuminated.  
   
   
       82 . The apparatus according to  claim 79  wherein the illuminating optics system provides modulated illuminating light.  
   
   
       83 . The apparatus according to  claim 79  wherein the illuminating optics system provides illuminating light utilizing serially applied tests.  
   
   
       84 . The apparatus according to  claim 79  the illuminating optics system further adapted to provide illuminating light into the eye to characterize the reflectance from the retina.  
   
   
       85 . The apparatus according to  claim 79  wherein the optical detector is a single element photodetector.  
   
   
       86 . The apparatus according to  claim 79  wherein the optical data analysis system calculates the blood glucose level using a look up table.  
   
   
       87 . The apparatus according to  claim 79  wherein the optical data analysis system calculates the blood glucose level using an algorithm.  
   
   
       88 . The apparatus according to  claim 79  wherein the optical data analysis system calculates the blood glucose level using a regression model.  
   
   
       89 . The apparatus according to  claim 79  further comprising: 
 (a) data storage comprising patient calibration data.    
   
   
       90 . The apparatus according to  claim 89  wherein the patient calibration data is combined with an algorithm carried out in the optical data analysis system to calculate the blood glucose level.  
   
   
       91 . The apparatus according to  claim 89  wherein the data storage is further adapted to receive updated patient calibration data.  
   
   
       92 . The apparatus according to  claim 79  wherein the optical data analysis system is configured to provide an output for storage, display or communication.  
   
   
       93 . The apparatus according to  claim 92  wherein the output comprises a readout of glucose concentration history.  
   
   
       94 . The apparatus according to  claim 79  wherein the apparatus is configured to be a hand-held device.  
   
   
       95 . The apparatus according to  claim 79  wherein the optical data is processed at a remote location.  
   
   
       96 . The apparatus according to  claim 95  wherein the optical data is sent wirelessly to be processed at a remote location.  
   
   
       97 . The apparatus according to  claim 95  wherein the optical data is sent via an access link to be processed at a remote location.  
   
   
       98 . The apparatus according to  claim 79  wherein the illuminating optics system is arranged to help reduce the intensity of the light reflected from structures of the eye other than the retina.  
   
   
       99 . The apparatus according to  claim 79  wherein the illuminating optics system is adapted to provide polarized illuminating light into the eye.  
   
   
       100 . The apparatus according to  claim 79  wherein the apparatus is equipped with a method requiring reactivation of the apparatus after a limited number of uses.  
   
   
       101 . A method of determining the blood glucose concentration in an individual, comprising: 
 (a) non-invasively measuring a rate of depletion of a substance in the individual; and    (b) determining the blood glucose concentration in the individual from the measured depletion rate of the substance.    
   
   
       102 . The method according to  claim 101  wherein the step of non-invasively measuring is performed in the eye.  
   
   
       103 . The method according to  claim 102  wherein the step of non-invasively measuring is performed in the eye by illuminating the eye with light.  
   
   
       104 . The method according to  claim 103  wherein the step of non-invasively measuring is performed in the eye by illuminating the eye with light at a wavelength absorbed by the substance being depleted.  
   
   
       105 . The method according to  claim 104  wherein the substance being depleted is all-trans-retinal.  
   
   
       106 . The method according to  claim 104  wherein the substance being depleted is rod rhodopsin.  
   
   
       107 . The method according to  claim 104  wherein the substance being depleted is cone rhodopsin.  
   
   
       108 . A method of measuring the blood glucose concentration in a person, comprising: 
 (a) Providing an apparatus according to  claim 89;     (b) Deactivating the apparatus after the apparatus has processed optical data to calculate the blood glucose level a number of times; and    (c) Reactivating the apparatus by a health care provider.    
   
   
       109 . The method according to  claim 108  further comprising: 
 (d) Updating the patient calibration data in the data storage.    
   
   
       110 . The method according to  claim 109  wherein the updating step is performed by a health care provider using blood samples taken from the person.  
   
   
       111 . The method according to  claim 109  wherein the updating step is performed periodically.  
   
   
       112 . The method according to  claim 109  wherein the updating step is performed wirelessly.  
   
   
       113 . The method according to  claim 109  wherein the updating step is performed using an access link.  
   
   
       114 . A method for use in the determination of the blood glucose concentration in an individual, comprising: 
 (a) Measuring an indicium of glucose metabolism;    (b) Determining the blood glucose concentration from the measured indicium.    
   
   
       115 . The method according to  claim 114  wherein the measuring step is performed in the eye.  
   
   
       116 . The method according to  claim 114  wherein the indicium of the glucose metabolism is manifested by a change in reflectance.  
   
   
       117 . The method according to  claim 114  wherein the indicium of the glucose metabolism is detected by measuring light reflected from the retina.  
   
   
       118 . The method according to  claim 114  wherein the indicium of the glucose metabolism is represented by the regeneration of visual pigment.  
   
   
       119 . The method according to  claim 114  wherein the indicium of the glucose metabolism is represented by the depletion of visual pigment.