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Description  |
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BACKGROUND OF THE INVENTION
The present invention relates to the quantitative determination of
optically active substances in specimens and, more particularly, to
apparatus and methods for non-invasively determining the concentration of
optically active substances.
In a number of diseases, it is desirable to monitor levels of chemical
agents in the organs of patients in order to control their medication. In
processes for manufacture of biogenetic materials, it is desirable to
monitor chemical agents in the reactor to determine the progress of the
reaction. In either instance, monitoring of the agent without invasion of
the medium is desirable.
Diabetes mellitus is a chronic systemic disease characterized by disorders
in both the metabolism of insulin, carbohydrate, fat and protein and the
structure and function of blood vessels. Diabetes can result in
circulatory problems which may lead to kidney failure, heart disease,
gangrene and blindness. A major unanswered question in diabetes therapy is
whether improved blood glucose control will alleviate the long-term
complications of this disease.
Normoglycemia is difficult to achieve in diabetics because insulin
injections do not adequately mimic non-diabetic insulin secretion patterns
since there is no feedback control of insulin delivery rate according to
the prevailing glucose level. In the last few years, there has been an
intensive effort to improve metabolic control in diabetics by developing
more physiological strategies of insulin administration. Three important
approaches are (a) self-monitoring of blood glucose samples and adjustment
of insulin dosages based on the results, (b) electromechanical devices for
infusion of insulin and (c) transplantation of the pancreas or islets of
Langerhans.
As is known, glucose is the main circulating carbohydrate in the body. In
normal individuals, the concentration of glucose in blood is tightly
regulated, usually in the range between 80 and 120 mg/100 ml, during the
first hour or so following a meal. The hormone insulin, normally produced
by the pancreas' beta cells, promotes glucose transport into skeletal
muscle and adipose tissue as well as uptake of glucose by the liver for
storage as glycogen. In Diabetes mellitus, insulin production and/or
uptake is comprised and, consequently, blood glucose can elevate to
abnormal concentrations ranging from 300 to 700 mg/100 ml. Excess insulin
administration can cause severe hypoglycemia.
Although insulin deficiency can be ameliorated by treatment with diet,
insulin or oral hypoglycemic agents, these standard modes of therapy have
not been effective in preventing the development of chronic complications
involving the eye, the kidney, the peripheral nervous system, and the
peripheral arteries. Accurate determination of glucose levels in body
fluids, such as blood, urine, and cerebro-spinal fluid, is a major aid in
diagnosing and improving the therapeutic treatment of diabetes. It can
reduce the long-term risk for developing coronary artery disease, visual
impairment, renal failure, and peripheral vascular disease.
Colorimetric techniques have been developed to allow accurate
self-determination of blood glucose levels by diabetic individuals.
Although this method allows the patient to close the loop himself by
altering the amount of insulin injected or the type and amount of food
ingested, these methods are invasive and time consuming and they are
especially bothersome for children. In order to overcome some of these
limitations, several techniques have been proposed to continuously monitor
glucose levels in the body, such as electrocatalysis.
However, there are major problems with the development of clinically useful
continuous glucose sensors. In general, implanted sensors operate in the
chemically and biologically harsh environment of the body for long periods
of time. As such, they are subject to continuous fibrotic encapsulation
and degradation which may raise questions about potential real-time
responsiveness without significant delay, and the capability for
integration with a pump.
Although implantation of an artificial endocrine pancreas and/or successful
transplantation of islet tissue remain long range goals for improving the
management of diabetes, the development of practical semi-invasive or
non-invasive means for monitoring blood glucose levels could provide, if
properly connected with an insulin pump through an appropriate controller,
much of the potential benefit of these methods without the hazards of
rejection and immunosuppression. Lastly, a noninvasive glucose sensor
could have significant application in the diagnosis and management of
Diabetes mellitis independently of the glucose pump controller
applications.
An optical sensing approach using polarization rotation has been described
by Rabinovitch, B., March, W. F., and Adams, R. L., in "Noninvasive
Glucose Monitoring of the Aqueous Humor of the Eye; Part 1. Measurement of
Very Small Optical Rotations", Diabetes Care, Vol. 5, No. 3; pp. 254-58,
May-June 1982, and in "Noninvasive Glucose Monitoring of the Aqueous Humor
of the Eye: Part II. Animal Studies and the Scleral Lens," Diabetes Care,
Vol. 5, No. 3; pp. 259-65, May-June 1982. In their work it was found that
measurement of glucose concentration in the aqueous humor of the eye
correlated well with blood glucose levels with a minor time delay on the
order of minutes. The glucose concentration in the aqueous humor was also
found to be two orders of magnitude higher than any other optically active
substances which were detected. A review of their work shows use of an
amplitude measurement which is subject to a number of problems including
noise susceptibility which limits the accuracy of the method.
The treatment of diabetes with prescribed injections of insulin
subcutaneously results in inadequate control of glycemia compared to
normal homeostatic control. Blood glucose levels rise and fall several
times a day and, therefore, normoglycemia using an "open-loop" insulin
delivery approach is difficult to maintain. An alternative solution to
this problem would be to "close the loop" using a self-adapting insulin
infusion device with a glucose biosensor which continuously detects the
need for dispensing insulin at the correct rate and time.
There have been major advances in the development of reliable, versatile,
and accurate insulin pumps. As mentioned, significant progress has also
been made toward the development of various glucose sensors, particularly
in terms of the electrocatalytic (Peura, R. A. and Mendelson, Y., "Blood
Glucose Sensors: An Overview". IEEE/NSF Symposium on Biosensors: pp.
63-68, 1984; and Lewandowski, J. J., Malchesky, P. S., Zborowski, M., and
Nose, Y., "Evaluation of a Miniature Blood Glucose Sensor", ASAIO Trans.,
34(3); pp. 255-58, Jul.-Sep. 1988), electroenzymatic (Clark, L. C., and
Noyes, L. K., "Theoretical and Practical Bases for Implantable Glucose
Sensors with Special Reference to the Peritoneum", IEEE/NSF Symposium on
Biosensors; pp. 69-74, 1984; Clark L. C. and Duggan, C. A., "Implanted
Electroenzymatic Glucose Sensors", Diabetes Care, Vol. 5, No. 3, pp.
174-80, May-Jun. 1982), and various optical (Regnault, W. F., and
Picciolo, G. L., "Review of Medical Biosensors and Associated Materials
Problems:, J. Biomed Mater. Res., Applied Biomaterials Vol. 21, No. A2;
pp. 163-80, 1987, - Rabinovitch, B., March, W. F., and Adams, R. L.,
"Noninvasive Glucose Monitoring of the Aqueous Humor of the Eye; Part 1.
Measurement of Very Small Optical Rotations", Diabetes Care, Vol. 5, No.
3; pp. 254-58, May-Jun. 1982; and March, W. F., Rabinovitch, B., and
Adams, R. L., "Noninvasive Glucose Monitoring of the Aqueous Humor of the
Eye: Part II. Animal Studies and the Scleral Lens."Diabetes Care, Vol. 5,
No. 3, pp. 259-65, May-Jun. 1982).
However, there remain major obstacles to the development of clinically
useful continuous glucose sensors. According to the National Diabetes
Advisory board, in the National Long-Range Plan to Combat Diabetes,
"Without a question, the most important long-term advance yet to be made
is the development of a continuous blood glucose sensor." The National
Institute of Diabetes, Digestive and Kidney Diseases (NIDDI) specifies
that an ideal glucose sensor should include: "(a) accuracy and ability to
distinguish blood glucose levels throughout the physiologic range; (b)
real-time responsiveness without significant delay; (c) biocompatability
and reliability for long periods: (d) small and easily implantable: (e)
capability for integration with suitable pump system." (Department of
Health and Human Services, Solicitation of the Public Health Service and
the Health Care Financing Administration for Small Business Innovation
Research (SBIR) Contract Proposals, PHS/HCFA 89-1, Due Date Dec. 9, 1988).
The principal object of the present invention is to provide a novel
non-invasive optically based sensor for quantitative determination of
optically active substances in a specimen.
It is also an object to provide such a sensor which exhibits a high degree
of accuracy and which may be adapted for use with various types of
specimens.
A specific object is to provide such a sensor which may be used for
determination of glucose levels by measurement of the level in the aqueous
humor.
A further object is to provide a novel and accurate non-invasive method for
determination of the quantity of optically active substances in specimens.
SUMMARY OF THE INVENTION
It has now been found that the foregoing and related objects may be readily
attained in an optically based apparatus for non-invasively determining
concentration of optically active substances in a specimen. The apparatus
includes a source of a beam of spatially coherent light, means for acting
upon the light beam to produce a rotating linear polarized vector therein,
and a beam splitter for splitting the beam into a reference beam and a
detector beam for passage through the specimen. It also includes means for
receiving the detector beam upon exiting the specimen, means comparing the
reference beam with the received detector beam to determine the amount of
phase shift produced by passage through the specimen, and means for
converting the amount of phase shift determined into concentration of the
optically active substance in the specimen.
Preferably, the means for producing the vector comprises a linear polarizer
for linearly polarizing the light beam, a circular polarizer for
circularly polarizing the linearly polarized beam, and a rotating linear
polarizer for producing a constant amplitude time varying linear
polarization in the beam. The linear polarizer polarizes the light beam to
produce the field
E=E.sub.o a.sub.x e.sup.j(.omega.t-kz)
wherein
E.sub.o =amplitude of wave
a.sub.x =unit vector in the x direction
e=base of natural logarithm
j=square root of -1
.omega.=frequency of the light
t=time in seconds
k=wave number
z=distance in the direction of propagation
The circular polarizer produces a light beam with a field, using vector
notation:
##EQU1##
Lastly, the means for producing a rotating linear polarization vector
operates at a frequency of .omega..sub.r /2 to produce a field described
as:
##EQU2##
Generally, the reference beam is passed to a stationary linear polarizer,
and there may be included a beam transport system for the detector beam
from the splitter to the specimen which may include optical fibers. For
optimum collimation and a limited spectrum, the light source is preferably
a laser.
In a particularly useful application the specimen is the aqueous humor in
the anterior chamber of the eye, which is behind the cornea and the
optically active substance is glucose. To increase the path and thereby
the accuracy, the apparatus desirably includes means for passing the beam
through the specimen two or more times.
In the method for non-invasively sensing levels of optically active
substances in a specimen, a beam of spatially coherent light is generated,
a rotating linear polarized vector is produced in the light beam, after
which the beam is split into a reference beam and a detector beam. The
detector beam is passed through the specimen, the detector beam exiting
the specimen is received and compared with the reference beam to determine
the amount of phase shift produced by passage through the specimen. The
amount of phase shift is then converted into a concentration value of the
optically active substance in the specimen.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a diagrammatic illustration of non-invasive apparatus embodying
the present invention for measuring glucose concentration in the aqueous
humor;
FIG. 2 is a diagrammatic illustration of another embodiment of non-invasive
apparatus for the same application;
FIG. 3 is an enlarged diagrammatic illustration of an eye with the detector
beam passing therethrough and including a passive contact lens;
FIG. 4 is a diagrammatic illustration of one embodiment of an apparatus for
providing a multiple pass of the detector beam through the eye; and
FIG. 5 is a graphic plot of observed test results and theoretical values
for rotation by passage through a glucose solution.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENT OF THE INVENTION
As indicated hereinbefore, the apparatus and method of the present
invention are based upon measurement of the phase shift in a polarized
light beam passed through a specimen containing an optically active
substance.
A principal objective of this development is the development of an
optically based sensor to monitor in vivo glucose concentrations to
facilitate the goal of diabetes therapy in approximating the 24 hour blood
glucose profile of a normal individual. There have been major advances in
the development of reliable, versatile, and accurate pumps for the
delivery of insulin to diabetic patients and control algorithms for
closed-loop delivery.
The polarization vector of light rotates when it interacts with an
optically active material such as glucose. The amount of rotation of
polarization is directly proportional to glucose concentration and to the
path length. The ability to quantitify blood glucose levels with the
limited available path length in the anterior chamber of the eye depends
on the signal-to-noise ratio of the polarization detector and the
sensitivity to measure physiologic glucose levels for the approximate one
centimeter path length present in the aqueous humor of the eye.
The present invention basically utilizes a true phase technique which uses
a rotating linear polarizer coupled with two stationary linear polarizers
and two detectors to produce reference and signal sinusoidal outputs whose
phase is equal to the rotation of light caused by the glucose solution.
The sensor may also include a null point technique which uses a Faraday
rotator and/or a passive contact lens for possible alignment and
correction of the beam. A bidirectional technique for correction of the
beam and doubling of the angle of rotation due to glucose may be used as
well as optical fibers, which make it feasible to transport coherent light
to and from the sensing site. The bidirectional approach couples light
into both sides of the eye. The output from each side may then be compared
to yield a doubled rotation angle due to glucose, and several techniques
potentially may be used to reduce sensitivity to optical rotation or
birefringence present in the cornea.
By inducing rotation of the linear polarization vector of the beam, it is
possible to reduce the detection of change in beam polarization to a
measurement of phase shift in the output beam as opposed to the
measurement of amplitude variations. This method of measurement provides
the opportunity for a large improvement in the signal-to-noise ratio by
eliminating amplitude variations due to fluctuations in the light source
or due to interaction of the optical beam with particulate matter. This
may potentially eliminate the major contributor of corneal optical
rotations or corneal birefringence.
Turning first to FIG. 1, therein illustrated is apparatus embodying the
present invention. A coherent light source 10, currently a helium neon
laser, emits a collimated beam 12. This could be a laser operating at a
different frequency (i.e., infrared diode) or a coherent light source with
a collimating lens. The beam 12 is then passed through a polarizing sheet
14 which linearly polarizes the light of the beam 12 to produce the
following field:
E=E.sub.o a.sub.x e.sup.j(.omega.t | | |
