U.S. patent application number 11/005767 was filed with the patent office on 2005-05-12 for non-invasive measurement of blood analytes using photodynamics.
Invention is credited to Rice, Mark J., Routt, Wilson.
Application Number | 20050101847 11/005767 |
Document ID | / |
Family ID | 26684155 |
Filed Date | 2005-05-12 |
United States Patent
Application |
20050101847 |
Kind Code |
A1 |
Routt, Wilson ; et
al. |
May 12, 2005 |
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.
Inventors: |
Routt, Wilson; (Lexington,
KY) ; Rice, Mark J.; (Johnson City, TN) |
Correspondence
Address: |
WILSON SONSINI GOODRICH & ROSATI
650 PAGE MILL ROAD
PALO ALTO
CA
943041050
|
Family ID: |
26684155 |
Appl. No.: |
11/005767 |
Filed: |
December 6, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11005767 |
Dec 6, 2004 |
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10642104 |
Aug 15, 2003 |
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10642104 |
Aug 15, 2003 |
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10012902 |
Oct 22, 2001 |
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6650915 |
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60318850 |
Sep 13, 2001 |
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Current U.S.
Class: |
600/319 ;
600/316; 600/365 |
Current CPC
Class: |
A61B 5/14558 20130101;
A61B 5/1455 20130101; A61B 5/14532 20130101; A61B 3/12
20130101 |
Class at
Publication: |
600/319 ;
600/316; 600/365 |
International
Class: |
A61B 005/00 |
Claims
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.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of prior application Ser.
No. 10/012,902, filed Oct. 22, 2001, which claimed priority from
provisional application No. 60/318,850, filed Sep. 13, 2001, which
are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention pertains to the field of non-invasive in vivo
measurement of blood analytes.
BACKGROUND OF THE INVENTION
[0003] The measurement of blood glucose by diabetic patients has
traditionally required the drawing of a blood sample for in vitro
analysis. The blood sampling is usually done by the patient himself
as a finger puncture, or in the case of a child, by an adult. The
need to draw blood for analysis is undesirable for a number of
reasons, including discomfort to the patient, resulting in many
patients not testing their blood as frequently as recommended, the
high cost of glucose testing supplies, and the risk of infection
with repeated skin punctures.
[0004] Many of the estimated three million Type 1 juvenile)
diabetics in the United States are asked to test their blood
glucose six times or more per day in order to adjust their insulin
doses for tighter control of their blood glucose. As a result of
the discomfort, many of these patients do not test as often as is
recommended by their physician, with the consequence of poor blood
glucose control. This poor control has been shown to result in
increased complications from this disease. Among these
complications are blindness, heart disease, kidney disease,
ischemic limb disease, and stroke. In addition, there is recent
evidence that Type 2 (adult-onset) diabetics (numbering over 10
million in the United States) may reduce the incidence of
diabetes-related complications by more tightly controlling their
blood glucose. Accordingly, these patients may be asked to test
their blood glucose as often as the Type 1 diabetic patients.
[0005] It would thus be desirable to obtain fast and reliable
measurements of the blood glucose concentration through simple,
non-invasive testing. Prior efforts have been unsuccessful in the
quest for a sufficiently accurate, non-invasive blood glucose
measurement. These attempts have involved the passage of light
waves through solid tissues such as the fingertip and the ear lobe
and subsequent measurement of the absorption spectra. These efforts
have been largely unsuccessful primarily due to the variability of
absorption and scatter of the electromagnetic energy in the
tissues. Other groups have attempted blood glucose measurement in
body fluids such as the anterior chamber, tears, and interstitial
fluids. To date, these efforts have not been successful for a
variety of reasons.
SUMMARY OF THE INVENTION
[0006] The present invention combines the accuracy of in vitro
laboratory testing of analytes such as blood glucose with the
advantages of a rapidly-repeatable non-invasive technology. The
invention utilizes a hand-held instrument that allows non-invasive
determination of glucose by measurement of the regeneration rate of
rhodopsin, the retinal visual pigment, following a light stimulus.
The rate of regeneration of rhodopsin is dependent upon the blood
glucose concentration, and by measuring the regeneration rate of
rhodopsin, blood glucose can be accurately determined. This
invention exposes the retina to light of selected wavelengths in
selected distributions and subsequently analyzes the reflection
from the exposed region.
[0007] The rods and cones of the retina are arranged in specific
locations in the back of the eye, an anatomical arrangement used in
the present invention. The cones, which provide central and color
vision, are located with their greatest density in the area of the
fovea centralis in the retina. The fovea covers a circular area
with a diameter of about 1.5 mm, with a subtended angle of about 3
degrees. The rods are found in the more peripheral portions of the
retina and contribute to dim vision.
[0008] The light source in the invention that is used to generate
the illuminating light is directed on the cones by having the
subject look at the light. This naturally provides for the incident
light striking the area of the retina where the cones (with their
particular rhodopsin) are located. The incoming light preferably
subtends an angle much greater than the angle required to include
the area of the fovea centralis, so that the entire reflected
signal includes the area of high cone density.
[0009] The invention uses light that varies in a selected temporal
manner, such as a periodically applied stimulus of light (for
example, a sinusoidal pattern), and then analyzes the reflected
light from the retina to determine the distortion of the detected
light relative to the illuminating light. The excitation format
chosen allows removal of the light signal due to passive
reflection. For example, the primary frequency of an applied
sinusoidal stimulus can be filtered out of the light received back
from the eye, leaving higher order harmonics of the fundamental as
the input into the analysis system (for example, a neural network).
Measurement of unknown blood glucose concentration is accomplished
by development of a relationship between these input data and
corresponding clinically determined blood glucose concentration
values.
[0010] Similarly, this technique can be utilized in the analysis of
photoreactive analytes such as bilirubin. Bilirubin is a molecule
that is elevated in a significant number of infants, causing
newborn jaundice. It would be desirable to non-invasively measure
bilirubin, as this is currently done with invasive blood testing.
This molecule absorbs light at 470 nm and exhibits a similar
photo-decomposition to rhodopsin, but without regeneration. In a
manner similar to that described above for rhodopsin measurement,
bilirubin may be measured utilizing a time-varying light signal and
analyzing the corresponding reflected light signals for non-passive
responses due to photo-decomposition. More generally, an
analysis--model-based or statistical--of descriptors (amplitude,
polarization, transient or harmonic content) of incident and
detected light can be carried out to determine a variation in the
detected signal resulting from light-induced changes in the
physical or chemical interaction of a photoreactive analyte with
the illuminating light.
[0011] In accordance with the invention, a hand-held or stationary
instrument that measures the resulting data in the reflected light
from a periodically applied light stimulus (for example, a
sinusoid) may be utilized for the determination of blood glucose
values. There may be patient-to-patient variability and each device
may be calibrated for each patient on a regular interval. This may
be necessary as the changing state of each patient's diabetes
affects the outer segment metabolism and thus influences the
regeneration rates of rhodopsin. The intermittent calibration of
the device is useful in patient care as it facilitates the diabetic
patient returning to the health-care provider for follow-up of
their disease. The device may be equipped with a method of limiting
the number of tests, so that follow-up will be required to
reactivate the device.
[0012] In the present invention, the reflected light data may be
sent to a central computer by a communications link in either a
wireless or wired manner for central processing of the data. The
result may then be sent back to the device for display or be
retained to provide a historical record of the individual's blood
glucose levels.
[0013] Further objects, features, and advantages of the invention
will be apparent from the following detailed description when taken
in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] In the drawings:
[0015] FIG. 1 is a schematic diagram of an apparatus for
measurement of the concentration of blood glucose in accordance
with the invention.
[0016] FIG. 2. is a schematic diagram of the preferred embodiment
of the illumination and optical system of the apparatus of FIG.
1.
[0017] FIG. 3 is an illustrative diagram of the amplitude of the
input signal from the illumination source.
[0018] FIG. 4 is a graph illustrating the results of a mathematical
simulation of the time response of the light-related biochemistry
reflected from the fovea centralis.
[0019] FIG. 5 is a graph of the harmonic content of the reflected
light from the fovea centralis.
[0020] FIG. 6 is a schematic side view of a hand-held measurement
system that may be utilized in accordance with the invention.
[0021] FIG. 7 is a schematic diagram of another embodiment of an
illumination and optical system that may be utilized in the
invention.
[0022] FIG. 8 is a schematic diagram of an embodiment of an
illumination and optical system utilizing a polarizing cube
beamsplitter for reducing the effect of unscattered
reflections.
[0023] FIG. 9 is a schematic diagram of an embodiment of an
illumination and optical system utilizing a reflecting mirror with
an aperture for reducing the effect of unscattered reflections.
DETAILED DESCRIPTION OF THE INVENTION
[0024] Rhodopsin is the visual pigment contained in the rods and
cones of the retina. As this pigment absorbs light, it breaks down
into intermediate molecular forms and initiates a signal that
proceeds down a tract of nerve tissue to the brain, allowing for
the sensation of sight. The outer segments of the rods and cones
contain large amounts of rhodopsin, stacked in layers lying
perpendicular to the light incoming through the pupil. There are
two types of rhodopsin, with a slight difference between the
rhodopsin in the rods (that allow for dim vision) and the rhodopsin
in the cones (that allow for central and color vision). Rod
rhodopsin absorbs light energy in a broad band centered at 500 nm,
whereas there are three different cone rhodopsins having broad
overlapping absorption bands peaking at 430, 550, and 585 nm.
[0025] Rhodopsin consists of 11-cis-retinal and the protein opsin,
which is tightly bound in either the outer segment of the cones or
rods. 11-cis-retinal is the photoreactive portion of rhodopsin,
which is converted to all-trans-retinal when a photon of light in
the active absorption band strikes the molecule. This process goes
through a sequence of chemical reactions as 11-cis-retinal
isomerizes to all-trans-retinal. During this series of chemical
steps, the nerve fiber, which is attached to that particular rod or
cone, undergoes a stimulus that is perceived in the brain as a
visual signal.
[0026] Following the breakdown of 11-cis-retinal to
all-trans-retinal, the 11-cis-retinal is regenerated by a series of
steps that result in 11-cis-retinal being recombined with opsin
protein in the cell or disk membrane. A critical step in this
regeneration pathway is the reduction of all-trans-retinal to
all-trans-retinol, which requires NADPH as the direct reduction
energy source. In a series of experiments, Futterman et al have
proven that glucose, via the pentose phosphate shunt (PPS),
provides virtually all of the energy required to generate the NADPH
needed for this critical reaction. S. Futterman, et al.,
"Metabolism of Glucose and Reduction of Retinaldehyde Retinal
Receptors," J. Neurochemistry, 1970, 17, pp. 149-156. Without
glucose or its immediate metabolites, no NADPH is formed and
rhodopsin cannot regenerate.
[0027] There is strong evidence that glucose is a very important
energy substrate for the integrity and function of the retinal
outer segments. It has been known since the 1960s that glucose and
glycolysis (the metabolism of glucose) are important in maintaining
the structure and function of the retinal outer segments. More
recently, it has been discovered that one of the major proteins
contained in the retinal outer segments is
glyceraldehyde-3-phosphate dehydrogenase, an important enzyme in
glucose metabolism. This points to the importance of glucose as the
energy source for the metabolism in the retinal outer segments,
which has as its primary function the maintenance of high
concentrations of rhodopsin.
[0028] In addition, Ostroy, et al. have proven that the
extracellular glucose concentration has a major effect on rhodopsin
regeneration. S. E. Ostroy, et al., "Extracellular Glucose
Dependence of Rhodopsin Regeneration in the Excised Mouse Eye,"
Exp. Eye Research, 1992, 55, pp. 419-423. Since glucose is the
primary energy driver for rhodopsin regeneration, the present
invention utilizes this principle to measure extracellular glucose
concentrations.
[0029] Furthermore, recent laboratory work by Ostroy et al has
shown that the retinal outer segments become acidic with chronic
elevated blood glucose concentrations. S. E. Ostroy, et al.,
"Decreased Rhodopsin Regeneration in Diabetic Mouse Eyes," Invest.
Ophth. and Visual Science, 1994, 35, pp. 3905-3909; S. E. Ostroy,
et al., "Altered Rhodopsin Regeneration in Diabetic Mice Caused by
Acid Conditions Within Rod Receptors," Current Eye Research, 1998,
17, pp. 979-985. Work in McConnell's laboratory has characterized
the retinal outer segments with these diabetic pH changes. It has
been noted that with increasing acidity of the retinal outer
segments, there exist pronounced changes in the light scattering by
the cells. These experiments reveal that as blood glucose increases
intracellular pH decreases. These changes affect the absorption
spectra and the light scattering properties of these cells and are
directly determined by intracellular glucose concentration. This
scattering effect is measured with the present invention and adds
an additional variable in the reflection of light, driven by the
glucose concentration, providing for even further accuracy with
this invention.
[0030] The following is an analysis of the photodynamic reactions
associated with the present invention:
[0031] Define:
[0032] R.sub.0=molecules/unit volume of rhodopsin
[0033] R.sub.1=molecules/unit volume of all-trans-retinal
isomer
[0034] G=molecules/unit volume of cytosol (intracellular)
glucose
[0035] G.sub.0=molecules/unit volume of extracellular glucose
[0036] L=photons/cm.sup.2 sec incident on the fovea
[0037] Recognizing that there are other photodynamic reactions
involved, a simple and conceptually accurate representation of the
rhodopsin cycle is given by the following equations:
dR.sub.0/dt=-k.sub.1R.sub.0L+k.sub.2R.sub.1G Equation 1
dR.sub.1/dt=k.sub.1R.sub.0L-k.sub.2R.sub.1G Equation 2
dG/dt=k.sub.3(G.sub.0-G)-k.sub.2R.sub.1G Equation 3
[0038] An auxiliary equation links the observed reflectance,
R.sub.F, of the foveal region to R.sub.0. Let R.sub.F min be the
reflectance under the filly bleached conditions and R.sub.F max be
the reflections when unbleached. Then the foveal reflectance is
approximately:
R.sub.F=R.sub.F min+(R.sub.F max-R.sub.F
min)e.sup.-k.sup..sub.4.sup.(R.su-
p..sub.dark.sup.-R.sup..sub.0.sup.) Equation 4
[0039] where:
[0040] R.sub.F max reflection at near dark conditions
[0041] R.sub.F min reflection at fully bleached conditions
[0042] R.sub.dark maximum value of R.sub.0
[0043] The R.sub.F min value is reflectance of the pigment
epithelium, which is a dark layer of tissue directly underneath the
rods and cones. R.sub.F max is determined by the optical
characteristics of the absorption process. R.sub.dark and k.sub.4
can be determined from historical measurement data. The point is
that foveal reflectance varies in a predictable way with R.sub.0
and hence with L and G. This variation is exploited in the present
invention to remove noise during analysis of reflected light; if
the fovea is exposed to sinusoidally varying amplitude of light,
then, because of the above noted variation of reflectance, the
reflected light will contain harmonics of the frequency of
variation of the incident light for the foveal reflections which
vary with bleaching. All the passively reflected light will have
amplitude varying at the frequency of the incident light.
[0044] Since the harmonics of the incident light frequency contain
the needed information about R.sub.0, the fundamental frequency can
be removed by data filtering techniques. This restricts analyzed
data to light reflected from the active foveal cells, greatly
improving signal to noise ratios.
[0045] The data gathering and analysis process illuminates the
posterior retina with light capable of bleaching rhodopsin and
varies the light amplitude, preferably sinusoidally, at an
appropriate rate or frequency (or multiple rates). Light reflected
in part from the anterior retina is then examined for
intensity/amplitude at 2,3,4, etc. times the frequency of variation
of the incident light. The estimated amplitudes of the harmonics
are closely related to the bleaching process, which is known to
depend upon cellular glucose concentrations as discussed above.
Harmonic amplitudes can be related to measured glucose
concentrations with a number of regression techniques or by the use
of artificial neural network methods.
[0046] A simple example of this idea is the following:
[0047] Assume that foveal reflectance R.sub.F is linearly related
to incident light amplitude L: L=A sin 2.pi.ft, and R.sub.F=BL=AB
sin 2.pi.ft
[0048] Then, R.sub.FL=A.sup.2B sin.sup.22.pi.ft=A.sup.2B(1/2-1/2
cos 4.pi.ft)
[0049] The reflected light is thus seen to be a constant amplitude
component and a component varying with twice the incident
frequency.
[0050] With reference to the drawings, FIG. 1 illustrates a glucose
analysis apparatus in accordance with the invention in conjunction
with the eye of a patient, with the eye shown illustratively at 10
in FIG. 1. The glucose analysis apparatus includes an illumination
and optics system 15 comprised of a light source and lens system
for projecting illuminating light onto the fundus, directly through
the pupil, and for receiving the light reflected from the fundus
passed out through the pupil. The lenses preferably include a final
lens which can be positioned close to the cornea of the eye,
providing a 5 to 30 degree conical view of the retina to be
illuminated and the light reflected back to the illumination and
optics system 15.
[0051] The illuminating light from the illumination and optics
system 15 includes a time varying (modulated) light amplitude
(preferably sinusoidal) added to (constant) amplitude of at least
half of the sinusoidal peak to peak value, as illustrated in FIG.
3. The wavelength range of the illuminating light preferably
matches the active range of the rhodopsin molecules illuminated.
Several frequencies of modulation of the illumination light from
the illumination and optics system 15, e.g., three frequencies of
input light, are preferably utilized in serially applied tests to
provide multiple sets of information to characterize the
reflectance from the retina. Illumination light may be provided by
various light sources, for example, a xenon light, a light emitting
diode (LED), or a halogen light source. LED illumination is
preferred because of the ease of varying the intensity of the light
from the LED by varying the input power to the LED. Alternatively,
steady state sources may be used with light modulators to provide
the appropriate time varying illumination. The patient being tested
may be directed to look directly at the light source, and by
centering the field of view on the incoming light, the appropriate
area of the fundus (fovea centralis) will be illuminated. Since the
area of interest is small compared to the area that is illuminated,
it is generally not critical that the illuminating light strikes
the fundus at any particularly exact area of the retina.
Furthermore, since the area of interest is in the approximate
center of the area illuminated, the correct area is easily
illuminated. Although the invention may be carried out with a
dilated eye pupil, it is an advantage of the present invention that
the testing can be carried out without requiring dilation of the
pupil for speed of measurement and patient convenience.
[0052] The illuminating light reflected from the fundus of the eye
10 passes out through the pupil opening of the eye to the
illumination and optics system 15, entering a (preferably) single
element photodetector 16, as illustrated in FIG. 1. Optical data
(e.g., in the form of an analog electrical signal or a digitized
signal) from the single element photodetector 16 is provided to the
optical data analysis system 17, where the information on the
reflected light is processed with, e.g., a phase-locked loop at 2,
3, and 4 times the light input modulation frequency. This provides
analysis of the higher order harmonics, which will be described in
more detail below.
[0053] The data in the reflected primary frequency of light
(containing noise including optical system and eye reflections) is
preferably not used. Only harmonics of the primary frequency are
preferably utilized as data input to a processor that carries out a
calculation of the blood glucose concentration. There are various
methods to eliminate the primary frequency of light including
passive filtering, phase lock loop, and many digital processing
techniques. Alternatively, a signal analysis such as a fast Fourier
transform can be performed and subsequently only the higher
harmonics may be used as data input. An additional variable,
associated with the light scattering effect of chronically high
glucose concentrations on the outer segments of the retina, affects
the reflected light data and can be accounted for in the processing
of the data.
[0054] The optical reflectance measurements may then be correlated
with blood glucose concentration measurements. Fast Fourier
Transforms (FFT) of the harmonic content data along with patient
calibration data from a data storage 18 may, for example, be
utilized in a neural network simulation carried out by computer.
Exemplary neural network and FFT analysis tools that may be used in
one embodiment of the invention are contained in the MATLAB.TM.
language and in the Neural Network Toolbox of MATLAB.TM. version
12.1. The neural network iteratively generates weights and biases
which optimally represent, for the network structure used, the
relationship between computed parameters of the detected light
signal and blood glucose values determined by the usual methods.
The desired relationship may be amenable, alternatively, to
development as a look-up table, regression model, or other
algorithm carried out in the optical data analysis system 17, e.g.,
a special purpose computer or an appropriately programmed personal
computer, work station, etc.
[0055] The relationship between the optical measurements made using
the apparatus of the invention and measurement made on blood
samples taken from the individual patient may change over a period
of time. The patient calibration data in the data storage 18 may be
combined with an algorithm carried out in the optical data analysis
system 17 to predict the specific patient's blood glucose
concentration, and the calibration data may be periodically
updated. The health-care provider may perform periodic calibration
of the apparatus at certain intervals, preferably every three
months.
[0056] The results of the calculated blood glucose concentration
from the optical data analysis system 17 are provided to an output
system 19 for storage, display or communication. A readout of the
glucose concentration history from a data history storage 20 may be
obtained by the health care provider at convenient intervals. The
blood glucose concentration may be directed from the output system
19 to a display 21 to provide for patient observation. This display
21 will be preferably by an LCD screen located on the device as
depicted as 21 in FIG. 6.
[0057] FIG. 2 shows a schematic diagram of a preferred embodiment
of the optical system 15. Illuminating sinusoidal light is
generated by an LED 13 and coupled to one leg of a dual branch
fiberoptic light guide 12. An example of an LED that may be used is
a Gilway E903 green LED, and the dual branch fiberoptic light guide
may be the Edmund Industrial Optics light guide #L54-200. The
illuminating light has wavelength content preferably consistent
with the wavelengths known to activate rhodopsin in areas of the
fovea illuminated by the incoming light. These preferred
wavelengths are in the range of 500 nm to 580 nm. This illuminating
light is amplitude modulated to a sinusoidal shape as depicted in
FIG. 3. Illuminating light from the LED 13 passes through the dual
branch fiberoptic light guide 12 and is delivered to a lens 11,
which then passes the light through the pupil of the eye 10 of the
patient and onto the retina. The retina, including the fovea
centralis, is flooded with illuminating light. The illuminating
light is then reflected from the retina, passes out through the
pupil, and enters the lens 11 where the light re-enters the light
guide 12. Since the light that enters the dual branch fiberoptic
light guide 12 near the lens 11 will be split at the y-portion of
the dual branch fiberoptic light guide 12, approximately 50% of the
reflected light will be presented to the photodetector 14. The
photodetector 14 of FIG. 2 corresponds to the single element
photodetector 16 of FIG. 1.
[0058] An alternative to the above-described embodiment of the
optical system includes a conventional lens system which is used to
direct the illumination light to the pupil and the returned
reflected light from the retina may be transported on this
conventional lens system (a common path). The reflected light may
then be directed to the photodetector by the use of a
beamsplitter.
[0059] Another embodiment of the optical system 15 is shown in FIG.
7. A hybrid device 28 is utilized that contains both an LED 13 and
a photodetector 14 in a common container. The LED 13 and the
photodetector 14 are optically isolated by a barrier 29. The lens
11 is positioned such that light from the LED 13 illuminates an out
of focus area on the retina, and that area is reflected onto the
photodetector 14. The operation of this optical system is the same
as described for FIG. 2 above.
[0060] FIG. 3 is a depiction of the input modulation signal for the
illumination source. The time varying signal is preferably a
sinusoid with a constant bias sufficient to prevent the waveform
from reaching zero signal. While a non-sinusoidal signal (e.g., a
square wave, etc.) or a signal reaching zero amplitude could be
used, the biased pure sinusoid (a sine wave and a constant
component) is preferred for simplicity of data analysis. The
wavelength of the illuminating light is preferably in the range of
500 nm to 600 nm, e.g., 550 nm, for analysis of glucose, although
other wavelength ranges may be utilized as appropriate. The
modulation frequencies of these input signals are preferably in the
range of 0.1 to 200 cycles per second (Hz) and multiple frequencies
may be utilized during the test period. The illuminating light is
preferably applied at different modulation frequencies during the
test period, for example, three sequential tests using 1, 3, and 10
Hz, a total test period of approximately 15 seconds and with 10
cycles test duration at each frequency.
[0061] FIG. 4 shows the results of a computer implemented
mathematical simulation of the individual responses of particular
molecules in the retina. Time is displayed on the abscissa (in
seconds), while the ordinate depicts the relative concentrations of
the particular analytes, shown as relative absorbance of light
energy. The upper curve models the response of the rhodopsin and
11-cis-retinal (the photoreactive portion) as the rhodopsin is
bleached by the sinusoidal illuminating light from the LED. The
lower curve simulates the concentrations of opsin and
11-trans-retinal, which regenerates into the 11-cis-retinal. The
middle curve reveals the consumption of the cytosol glucose, which
is the sole energy source for the regeneration of the
11-cis-retinal. The rates of bleaching and regeneration shown in
the upper and lower curves are driven by the amount of glucose
available in the cells to support regeneration.
[0062] FIG. 5 shows the results of a Fast Fourier Transform (FFT)
carried out on an example of data corresponding to light reflected
from the retina at one selected excitation frequency. The rhodopsin
content and the bleaching of rhodopsin can be measured by analyzing
the reflected light from the retina. Since the amount of reflected
light is a function of the amount of bleaching, and the amount of
bleaching is a function of the intensity of incoming light, the
reflection is a non-constant response and will contain harmonic
content. The primary reflected response is at the modulation
frequency of the LED light output. This primary frequency is
preferably filtered out, e.g., with a digital high pass filter that
is set to filter all frequency content less than twice the
illuminating frequency, because it contains noise generated by
reflections from the optical system and the layers of the eye. The
remaining higher order harmonics contain noise-free information and
are used as input data to a computer processing system, e.g.,
implementing a neural network, along with patient calibration data.
By training the neural network with data from a large number of
patients, the appropriate relationships and weighting factors are
determined. These values are used in development of an algorithm
that accurately predicts blood glucose concentrations from the
available information.
[0063] An illustration of a hand-held device embodying the
invention is shown in FIG. 6. This unit contains the elements
depicted in FIG. 1 and FIG. 2. The display 21 provides the glucose
concentration information to the patient, preferably utilizing an
LCD screen. An electrical connector 23 can be utilized by the
patient or healthcare provider to cable connect to a host system
that allows for reading out of the data history from the storage 20
(see FIG. 1) and updating of the patient calibration data in the
storage 18 (FIG. 1). A button 24 is provided to activate the unit
for data acquisition, in a manner similar to taking a photograph
with a standard camera. If desired, a disposable plastic cover can
be used to cover the lens 11 to minimize the spread of infectious
diseases. The hand-held unit is preferably self-contained and
contains batteries and memory.
[0064] The analysis of the reflected signal may take place at a
location remote from the clinical setting by using a wired or
wireless internet link (or dedicated communication link) to
transfer data from the photodetector to a central computer at a
remote location (e.g., anywhere in the world linked by the
internet) where the optical data analysis system 17 (see FIG. 1) is
implemented. The output data from the output system 19 may be
transferred back through an access link to the display of results
21 or to another location if desired.
[0065] The illumination and optics systems of FIGS. 2 and 7 provide
a means for projecting illuminating light into the eye with an
intensity varying periodically at a selected frequency and means
for detecting the light reflected from the retina and particularly
the fovea centralis to provide a signal corresponding to the
intensity of the detected light. Any other elements which similarly
project light into the eye and detect the reflected light may be
utilized. Examples of such alternative means are illustrated in
FIGS. 8 and 9, although it is understood that these are exemplary
only of such structures. The illumination and optics systems of
FIGS. 8 and 9 are arranged to help reduce the intensity of the
light reflected from structures of the eye other than the retina,
and particularly to reduce the effect of light reflected from the
surface of the cornea. In the illumination and optics system of
FIG. 8, the light projected from a source 31, such as an LED,
expands in a beam 32 which is received by a lens 33 which directs
the beam to a polarizing beamsplitter 35. The polarized beam 36
that exits the beamsplitter is passed through a lens 37 and an
eyepiece lens 38 to the eye 10 where the lens of the eye focuses
the beam onto the fovea 39 of the retina. The light reflected from
the retina and particularly the fovea 39 (and from other eye
structures such as the cornea 40) is directed back through the
eyepiece 38 and the lens 37 to the polarizing beamsplitter 35. The
polarized light reflected from the surface 40 of the cornea passes
through the beamsplitter 35 and is lost, while the scattered
(non-polarized) light resulting from reflection from the retina and
particularly the fovea 39 is reflected by the beamsplitter 35 into
a beam 42 which is focused by a lens 43 onto a photodetector 44
that provides an output signal on a line 45 corresponding to the
(time varying) intensity of the detected light. This signal may
then be analyzed to determine the magnitude of a harmonic or
harmonics of the frequency of variation of the illuminating
light.
[0066] In the illumination and optics system of FIG. 9, the light
from a source 48 (e.g., an LED) is projected in a beam 49 to a lens
50 which provides a collimated beam 51 to a mirror 53 which has a
central aperture 54 therein. The aperture 54 permits a central
portion 55 of the beam 51 to pass therethrough and be lost. The
rest of the beam 51 is reflected from the surface 56 of the mirror
53 into a beam 57 which is received by a focusing system composed
of a first lens 58 and a second lens 60 to provide an output beam
61 that passes through the cornea 40 of the eye 10 and is focused
by the lens of the eye onto the retina of the eye and particularly
the fovea 39. The light reflected from the retina and particularly
the fovea 39 passes back through the lens of the eye and the cornea
40 and into the optical system composed of the lenses 58 and 60,
which forms the light reflected from the fovea 39 into a beam 62 in
the center of the reflected beam. The beam of light 62 reflected
from the fovea is narrow enough to substantially pass through the
aperture 54 to a lens 64 which focuses the beam onto a
photodetector 65 that provides an output signal on a line 66
corresponding to the intensity of the detected light. The aperture
54 will appear as a dark spot in the field of view of the
individual being tested, and the light reflected from the fovea
will be naturally aligned with the aperture 54 by having the
individual focus on the dark spot in the field of view. In the
illumination and optics systems of FIG. 9, the light that reaches
the detector 65 is thus primarily the light reflected from the
fovea 39 in the relatively narrow beam portion 62, whereas the
light reflected from other structures in the eye, such as the
surface of the cornea 40, is contained in a broader reflected beam
that reaches the surface of the mirror 56 and is reflected thereby
rather than being passed through the aperture 54, again improving
the signal to noise ratio of the light reaching the detector
65.
[0067] It is understood that the invention is not confined to the
particular embodiments set forth herein for illustration, but
embraces all such forms thereof as come within the scope of the
following claims.
* * * * *