1. Field of the Invention
This invention relates to an improved optical method and/or sensor for polyhydroxy substituted organic molecules that measure the concentration of these molecules in aqueous or organic media. In one application, the method and sensor monitor the concentration of sugars, i.e. glucose or fructose, in aqueous solution in vitro. In particular, the method and sensor monitor the concentration of sugars, i.e. glucose or fructose, in aqueous solution in vivo. The determination of glucose in fluids in vivo and in vitro—is of importance. The in vivo sensing device is implanted in a human being. Some of the novel components of the optical method and device are also considered to be inventions in their own right.
2. Description of Related Art
There has been an ongoing effort over many years to use fluorescence techniques to measure polyhydroxyl compound (e.g. glucose) concentrations in body fluids. Although the term “glucose” is used herein below, it is to be understood that the concentration of most polyhydroxyl-containing organic compounds (carbohydrates, 1,2-diols, 1,3-diols and the like) in a solution are determined. But in spite of the intense effort, no practical system has been developed and commercialized for in vivo monitoring. Several attempts have been made to detect glucose by fluorescence using dyes to which a boronic acid group has been attached. Boronic acids are known to bind sugars reversibly. When the boronic acid functional dye binds to a sugar, the properties of the dye are affected. These changes have been used in the past to measure sugar concentration.
One use of this approach to a glucose sensor was reported by Russell, U.S. Pat. No. 5,137,833 (See also Russell & Zepp, U.S. Pat. No. 5,512,246) which disclosed the use of a boronic acid functionalized dye that binds to glucose and generates a signal dependent on glucose concentration. James et al U.S. Pat. No. 5,503,770 used the same principle but combined a fluorescent dye, an amine quenching functionality, and a boronic acid in a single complex moiety, the fluorescence emission from which varies with extent of glucose binding. Van Antwerp et al U.S. Pat. Nos. 6,002,954 and 6,011,984 combined features of the previously cited references and also taught fabrication of a device that is purported to be implantable. A. E. Colvin, Jr. in U.S. Pat. No. 6,304,766 disclosed optical-based sensing devices, especially for in-situ sensing in humans.                Patents of interest include but are not limited to:        Russell, U.S. Pat. No. 5,137,833 (1992)        James et al, U.S. Pat. No. 5,503,770 (1996)        Russell & Zepp, U.S. Pat. No. 5,512,246 (1996)        Van Antwerp et al, U.S. Pat. No. 6,002,954 (1999)        Van Antwerp and Mastrototaro, U.S. Pat. No. 6,011,984 (2000)        Related U.S. patents of interest include:        Wolfbeis et al, U.S. Pat. No. 4,586,518 (1986)        Gallop & Paz, U.S. Pat. No. 4,659,817 (1989)        Yafuso & Hui, U.S. Pat. No. 4,798,738 (1989)        Yafuso & Hui, U.S. Pat. No. 4,886,338 (1989)        Saaski et al, U.S. Pat. No. 5,039,491 (1991)        Lanier et al, U.S. Pat. No. 5,114,676 (1992)        Wolfbeis et al, U.S. Pat. No. 5,232,858 (1993)        Colvin, U.S. Pat. No. 5,517,313 (1996)        Sundrehagen et al, U.S. Pat. No. 5,631,364 (1997)        James et al, U.S. Pat. No. 5,763,238 (1998)        Siegmund et al, U.S. Pat. No. 5,711,915 (1998)        Bamard & Rouilly, U.S. Pat. No. 5,852,126 (1998)        Colvin, U.S. Pat. No. 5,894,351 (1999)        Alder et al, U.S. Pat. No. 5,922,612 (1999)        Arnold et al, U.S. Pat. No. 6,063,637 (2000)        Song et al, U.S. Pat. No. 6,046,312 (2000)        Kimball et al, U.S. Pat. No. 6,139,799 (2000)        Clark et al., U.S. Pat. No. 6,040,194 (2000)        Schultz, U.S. Pat. No. 6,256,522 (2001)        Walt, et al., U.S. Pat. No. 6,285,807 (2001)        Colvin U.S. Pat. No. 6,304,266 (2001)        Van Antwerp, et al., U.S. Pat. No. 6,319,540 (2001)        Related articles and publications of interest include:        Yoon & Czarnik, J. Amer. Chem. Soc. (1992) 114, 5874-5875        James, Linnane, & Shinkai, Chem. Commun. (1996), 281-288        Suenaga et al, Tetrahedron Letters (1995), 36, 4825-4828        Eggert et al, J. Org. Chem. (1999), 64, 3846-3852        Wolfbeis et al, Analytica Chimica Acta (1995), 304, 165-170        Wang et al, Organic Letters (1999), 1, 1209-1212        Chen et al, Proc. Nat. Acad. Sci. (1999), 96, 12287-12292        P. D. Hale et al, Analytica Chimica Acta (1999), 248, 155-161        A. E. Colvin, Jr. et al, Johns Hopkins Technical Digest, Vol. 12, #17, p. 378 (1996)        Cappucio, et al., J. Fluorescence, 2004, 14, 521-533.        Camara et al., Tetrahedron Letters, 2002, 43, 1139-141.        Suri, et al., Angewandte Chemie Int. Ed., 2003, 42, 5857-5859.        Suri, et al., Langmuir, 2003, 19, 5145-5152.        References of a general nature include:        A. W. Czarnik (ed), Fluorescent Chemosensors for Ion and Molecule Recognition, ACS Washington, D.C. 1992.        F. W. Scheller et al (eds), Frontiers in Biosensorics I Fundamental Aspects, Birkhauser Verlag, Basel 1997.        J. R. Lakowicz, Principles of Fluorescence Spectroscopy. 2nd ed. Kluwer        Academics/Plenum Publishers, New York, N.Y. (1999).        Haugland, R. P. Handbook of Fluorescent Probes and Research Chemicals 6th ed. Molecular Probes Inc. Eugene, Oreg. (1996).        Gunter Wulff, et al., “Molecular Imprinting for the Preparation of Enzyme Analogous Polymers”, pp. 10-28 in R. A. Bartsch and M. Maeda (eds) Molecular and Ionic Recognition with Imprinted Polymers. ACS Symposium 703 American Chemical Society 1998. Washington, D.C.        H. Murakami, et al, “Glucose Detection by Electrochemical Methods Using a Viologen Boronic Acid Derivative”, Chem. Letters (Japan), (2000) (8) p. 940-1.        Some references concerning the technology of the quantum dots include:        D. Ishii, et al., Nature 2003, 423, 628-632.        D. Larson, et al., Science 2003, 300, 1434-1436.        W. C. Chan, et al., Current Opinion in Biotechnology 2002, 13, 40-46.        W. C. Chan, et al., Science 1998, 281, 2016-2018.        C. Niemeyer, Angewandte Chemic-International Edition 2001, 40, 4128-4158.        M. Bruchez, et al., Science 1998, 28 I, 2013-2016.        S. L. Dgunov, et al., Journal of Physical Chemistry A 1995, 102, 5652-5653.        Y. Nosabi, et al., J Phys Chem 1988, 92, 255-256.        D. Duonghong, J. Am Chem Soc, 198 L 103, 4685-4690.        C. Landes, et al., Journal of Physical Chemistry 11 2001, 105. 29X!-29&6.        K. M. Gattas-Asfina et al., Immobilization of Quantum Dots in the Photo Crosslinked Poly(ethylene glycol)-based Hydrogel, J. Phys. Chem. B, 2003, 104, 10464-69.        
All patents, articles, references, standards and the like cited in this application are incorporated herein by reference in their entirety.
All of these prior art sensors are deficient in one or more aspects, such as operability under physiological conditions, stability of operation, simplicity of design, reliability, implantability, and sensitivity. The present invention overcomes these deficiencies.