Surgery – Diagnostic testing – Measuring or detecting nonradioactive constituent of body...
Reexamination Certificate
2000-06-09
2002-08-27
Winakur, Eric F. (Department: 3736)
Surgery
Diagnostic testing
Measuring or detecting nonradioactive constituent of body...
C600S322000, C600S316000
Reexamination Certificate
active
06442410
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally to the field of measuring the blood glucose levels of humans and, more specifically, to the field of measuring the blood glucose levels of humans using non-invasive techniques by measuring the optical refractivity of the ocular aqueous humor and comparing the measurements to known data.
BACKGROUND OF THE INVENTION
The potential for the non-invasive measurement of blood glucose concentration to improve the level of blood sugar control and the quality of life of diabetic patents has been recognized for nearly three decades. Cahill, G. F. et al, Practical Developments in Diabetes Research,
Diabetes
Vol. 21 (Supp. 2), pp. 703-712 (1972). However, the ability to realize highly reliable and robust instrumentation capable of such measurements has continued to prove an elusive goal.
The common thread among nearly all non-invasive techniques is the use of electromagnetic radiation to measure directly, or to infer indirectly, the blood glucose concentration. Numerous attempts have been made at non-invasive glucose measurement by directing electromagnetic radiation through the skin to measure blood glucose directly.
The most promising direct measurement approaches transmit radiation in the near infrared portion of the electromagnetic spectrum through the skin and estimate glucose concentration from the spectral signature of the absorption at selected wavelengths from 1-3 microns. In the 1-3 micron range, the absorption spectrum from water is not as dominant as at longer wavelengths, and there exist a number of unique, detectable features in the glucose absorption spectrum. Arnold, M. A.,
Handbook of Clinical Laboratory Automation, Robotics and Optimization
, Chapter 26 (ed. Kost), John Wiley & Sons, New York (1996); Burmeister, J. J. et al., Spectroscopic Considerations for Noninvasive Blood Glucose Measurements with Near Infrared Spectroscopy,
IEEE LEOS Newsletter
, Vol. 12, pp. 6-9 (1998). However, transdermal measurements are especially challenging given the variability in path length from measurement to measurement, and given the spectral complexity of the fatty tissue and the myriad of constituents contained in biofluids such as whole blood. Approaches for correcting for such effects are discussed by Burmeister and Arnold.
As an alternative, the ocular aqueous humor (in the anterior portion of the eye) contains far fewer constituents that would interfere with the spectroscopic detection of glucose. Lambert, J. et al., Measurement of Physiologic Glucose Levels Using Raman Spectroscopy in a Rabbit Aqueous Humor Model,
IEEE LEOS Newsletter
, Vol. 12, pp. 19-22 (1998); Wicksted, J. P. et al., Raman Spectroscopy Studies of Metabolic Concentrations in Aqueous Solutions and Aqueous Humor Specimens,
Applied Spectroscopy
, Vol. 49, pp. 987-993 (1995). Likewise, if the eye position can be held stable relative to the sensor, the path length through the anterior portions of the eye is quite stable.
Throughout the 1950's and 60's, a number of studies of the relationship between blood glucose levels and glucose levels in the aqueous humor were conducted. Kinsey, V. E. et al., Transport of Glucose Across Blood-Aqueous Barriers as Affected by Insulin,
Journal of Physiology
, Vol. 156, pp. 8-16 (1961); Pohoja, S., The Steady-State Ratio of Aqueous Glucose in Diabetic Hyperglycemia,
Acta Ophthalmologica [Supp.]
, Vol. 88, pp. 51-54 (1966). In vivo measurements showed a steady-state ratio of blood plasma glucose levels to aqueous humor levels of 1.05 in rabbits, and a ratio of approximately 1.8 for the two human patients tested. Reim, M. et al., Steady State Levels of Glucose in the Different Layers of the Cornea, Aqueous Humor, Blood and Tears In Vivo, Ophthalmologica, Vol. 154, pp. 39-50 (1967). This corresponds to a ratio of steady-state whole blood glucose concentration to aqueous ocular glucose concentration of approximately 1.6. Moreover, variations in blood glucose levels are reflected in corresponding variations in the concentration in the aqueous humor. Pohoja, S., The Glucose Content of the Aqueous Humor in Man,
Dissertation
, University of Helsinki (1966).
In the nearly three decades since Cahill et al, supra, suggested that some property such as refractive index or near-infrared absorbance could be measured and correlated with glucose level, a wide range of optical techniques have been promoted for determination of the glucose concentration in the aqueous humor. In U.S. Pat. No. 3,958,560 to March, use of a contact lens with an integrated infrared source, such as zirconium-filament light bulb, and a detector which would measure the amount of energy transmitted transversally through the cornea anterior to the iris and pupil is disclosed. In such a system, the enhanced absorption from the hydroxyl portion of the glucose molecule was thought to be measurable, and would be directly proportional to glucose abundance. March '560 also suggested that visible light might be introduced on the same transversal path and detected by an interferometer, which would measure the change in refractive index due to the refraction from glucose in the aqueous humor. The change in refractive index would likewise be proportional to glucose concentration in the aqueous humor. Unfortunately, neither effect was shown to be measurable using the technological approaches of the 1970's.
As an alternative, in U.S. Pat. No. 4,014,321 to March, a system which radiated polarized light on the transversal path through the cornea and then measured the change in polarization upon exit could be used to infer the glucose concentration in the aqueous humor since glucose is optically active is disclosed. This was especially attractive, since the majority of laser energy would not be directed toward the retina. The safe retinal exposure level for pulsed lasers in the near IR is on the order of 1-10 millijoules depending on pulse duration, with an exposure power limit of approximately to microwatts for continuous wave (CW) exposure. FDA Standards for Laser Safety, 21 C.F.R. Sec. 1040; Tarr, R. V. et al., The Non-Invasive Measure of D-Glucose in the Ocular Aqueous Humor using Stimulated Raman Spectroscopy,
IEEE LEOS Newsletter
, Vol. 12, pp. 22-27 (1998).
The use of optical polarimetry for measurement of ocular glucose has been a dynamic area of research of the past two decades. Results were reported from tests of an optical bench model of a polarimetric glucose sensor in which glucose concentrations as low 20 mg/dl were measured in a test cell. Rabinovitch, B. et al., Noninvasive Glucose Monitoring of the Aqueous Humor of the Eye: Part I. Measurement of Very Small Optical Rotations,
Diabetes Care
, Vol. 5, pp. 254-258 (1982). This corresponded to optical rotations of about only 40 arcseconds. The same optical bench model was used to measure glucose concentrations of rabbit ocular aqueous humor which was removed by paracentesis directly into a test cell. March, W. F. et al., Noninvasive Glucose Monitoring of the Aqueous humor of the Eye: Part II. Animal Studies and the Scleral Lens,
Diabetes Care
, Vol. 5, pp. 259-265 (1982). Work on an experimental scleral lens was also described in this study for non-invasive measurement of glucose concentrations in the aqueous humor of test animals, but the optical activity of constituents other than glucose, plus the birefringence of the cornea, made it extremely difficult to unambiguously infer the glucose concentration in the aqueous humor of the test animals.
In an attempt to correct for these problems, a multi-wavelength polarimeter, which has the potential to detect possible wavelength dependencies in the optical activity, which could then make it possible to separate the effects of the different constituents and to correct for birefringence in the cornea has been suggested. McNichols, R. J. et al., Development of a Non-Invasive Polarimetric Glucose Sensor,
IEEE LEOS Newsletter
, Vol. 12, pp. 30-31 (1998); Cote, G. L.,
Diabetes Technology and Therapeutics
, Vol. 1 (1999). The addition of optica
Deveau Todd
Georgia Tech Research Corp.
Kremer Matthew
Troutman Sanders LLP
Vorndran Charles
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