Non-invasive glucose measurement method and apparatus

Claims

What is claimed is:

1. A method of determining non-invasively and in vivo the concentration of blood glucose, said method comprising the steps of:

a) irradiating in vivo and non-invasively the eye with near-infrared energy having at least several wavelengths, the energy being reflected from at least one structure within the anterior portion of the eye and reemerging after having undergone differential absorption at least within the aqueous humor of at least some of said wavelengths characteristic of glucose and other constituents of the eye and their respective unknown concentrations;

b) measuring the spectral intensity of the near-infrared energy reemerging from the eye and producing electrical signals representative of said measured intensity; and

c) calculating the unknown concentration of blood glucose from variations of said measured intensity signals.

2. The method of claim 1 wherein said calculating step includes processing said measured intensity signals using multivariate modeling and calibration techniques.

3. The method of claim 1 wherein said near-infrared energy is broad band and optically encoded with respect to wavelength spectral information in a manner such as to be decodable after detection.

4. The method of claim 1 wherein said irradiating step includes the step of directing the near-infrared energy so that the specular reflection of the electromagnetic energy from the curved anterior surfaces of the cornea and sclera is not measured.

5. The method of claim 1 wherein said irradiating step includes the further step of substantially blocking extraneous light from the surrounding environment so it is not measured.

6. Apparatus for determining non-invasively and in vivo the concentration of blood glucose comprising:

means for irradiating in vivo and non-invasively an eye with near-infrared energy having at least several wavelengths, said energy being reflected from at least one structure within the anterior portion of eye and reemerging after having undergone differential absorption within the aqueous humor of at least some of said wavelengths characteristic of glucose and other constituents of the eye in relation to respective concentrations;

means for measuring the spectral intensity of the near-infrared energy reemerging from the eye and producing electrical signals representative of said measured intensity; and

means for calculating the concentration of blood glucose from variations of said measured spectral intensity signals.

7. The apparatus of claim 6 wherein said means for calculating includes means for processing said measured spectral intensity signals using multivariate modeling and calibration techniques.

8. The apparatus of claim 7 wherein said signals are classified as being appropriate for use and analyzed if appropriate to determine whether they conform to an applicable multivariate calibration model.

9. The apparatus of claim 6 wherein said irradiating means provides broad band infrared energy which is spectrally encoded in narrow wavelength bands, said measuring means operating to collect the reflected energy and convert it to a composite electrical signal representative of the energy at all wavelengths simultaneously; means being provided for decoding the composite electrical signals relating to the reflected energy at each of the multiplicity of narrow wavelength bands which comprise the broad band energy to the eye, said calculating means being responsive to said coded signals.

10. The apparatus of claim 9 wherein an interferometer is provided for spectral encoding of said near-infrared energy and said decoding means is a Fourier transform decoder.

11. The apparatus of claim 9 wherein a time-variable encoding mask placed in a dispersed spectral image is provided for spectral encoding of said near-infrared energy and said decoding means is a time sequence decoder.

12. The apparatus of claim 9 wherein said encoding means includes electrical modulation of multiple discrete sources, said decoding means being capable of separating the measured signal based on the modulation of the reflected energy.

13. The apparatus of claim 12 wherein said source are light emitting diodes.

14. The apparatus of claim 6 wherein said irradiating means and measuring means are configured and positioned to direct the specular reflection of the electromagnetic energy from the curved anterior surfaces of the cornea away from the detection means to prevent spectroscopic errors associated with the detection of energy which has not undergone absorption.

15. The apparatus of claim 6 wherein said measuring means is configured and positioned so that extraneous energy from the surrounding environment is substantially blocked from reaching said detection means.

16. The apparatus of claim 6 wherein said means for calculating includes means for processing said measured intensity signals by univariate modeling and calibration techniques.

17. The apparatus of claim 6 further including means for rapidly repeating the entire measurement sequence at a sufficiently high rate so that movement of the apparatus will not cause significant errors.

18. The apparatus of claim 6 further including means for providing a signal to the user to indicate that the signals obtained are suitable for processing.

19. The apparatus of claim 6 further including means for providing a signal to the user that sufficient acceptable signals have been accumulated, the glucose value is computed and that the measurement is complete.

20. Apparatus for determining non-invasively and in vivo the concentration of blood glucose comprising:

means for irradiating in vivo and non-invasively an eye with near-infrared energy having at least several wavelengths, said energy entering the eye and being reflected from at least one structure within the anterior portion of the eye and reemerging after having undergone differential absorption within the aqueous humor of at least some of said wavelengths characteristic of glucose and other constituents of the eye in relation to respective concentrations, said irradiating energy being modulated by modulating signals provided by modulating means;

means for measuring the spectral intensity of the near-infrared energy reemerging from the eye and producing electrical signals representative of said measured intensity;

means for calculating the concentration of blood glucose from variations of said measured spectral intensity signals; and

wherein said measuring means and calculating means are responsive only to energy modulated by said modulating signals while discriminating against interference signals.

21. Apparatus for determining non-invasively and in-vivo the unknown value of blood glucose comprising:

means for irradiating in vivo and non-invasively an eye with near-infrared energy having at least several wavelengths, said energy being reflected from at least one structure within the anterior portion of the eye and reemerging after having undergone differential absorption of at least some of said wavelengths characteristic of glucose and other constituents of the eye and their respective unknown concentration;

means for measuring the spectral intensity of the near-infrared energy reemerging from the eye and producing electrical signals representative of said measured intensity; and

means for calculating the unknown concentration of blood glucose from variations of said measured spectral intensity signals; and

including fixation means for producing visible light so directed as to provide a fixation point for a user, thereby aiding the user to maintain the proper location and orientation of the irradiating means and measuring means.

22. The apparatus of claim 21 wherein said fixation means provides visible light at an intensity to cause the pupil to contract thereby maximizing the reflecting area of the iris.

23. The apparatus of claim 21 wherein said fixation means provides a plurality of visible light sources in a pattern indicative of positioning errors and their direction, the light from which being at least partially blocked by the iris when the apparatus is correctly positioned.

24. A method of determining non-invasively and in vivo the concentration of blood glucose, said method comprising the steps of:

a) irradiating in vivo and non-invasively the eye with near-infrared energy having at least several wavelengths, said energy entering the eye and being reflected from at least one structure within the anterior portion of the eye and reemerging after having undergone differential absorption at least within the aqueous humor of at least some of said wavelengths characteristic of glucose and other constituents of the eye and their respective unknown concentrations;

b) measuring the spectral intensity of the near-infrared energy reemerging from the eye and producing electrical signals representative of said measured intensity, said measuring step including measuring the near-infrared energy reflected from the iris and reemerging from the eye; and

c) calculating the unknown concentration of blood glucose from variations of said measured intensity signals.

25. Apparatus for determining non-invasively and in vivo the concentration of blood glucose comprising:

means for irradiating in vivo and non-invasively an eye with near-infrared energy having at least several wavelengths, said energy being reflected from at least one structure within the anterior portion of the eye and reemerging after having undergone differential absorption within the aqueous humor of at least some of said wavelengths characteristic of glucose and other constituents of the eye in relation to respective concentrations;

means for measuring the spectral intensity of the near-infrared energy reemerging from the eye and producing electrical signals representative of said measured intensity, said measuring means operating to measure the spectral intensity of the near-infrared energy reflected from the iris and reemerging from the eye; and

means for calculating the concentration of blood glucose from variations of said measured spectral intensity signals.

26. A method of determining non-invasively and in vivo the concentration of blood glucose, said method comprising the steps of:

a) irradiating in vivo and non-invasively the eye with near-infrared energy having at least several wavelengths, the energy being reflected from at least one structure within the anterior portion of the eye and reemerging after having undergone differential absorption at least within the aqueous humor of at least some of said wavelengths characteristic of glucose and other constituents of the eye and their respective unknown concentrations.;

b) measuring the spectral intensity of the near-infrared energy reemerging from the eye and producing electrical signals representative of said measured intensity; and

c) calculating the concentration of blood glucose from variations of said measured intensity signals, and further including the step of providing a visible light fixation point for a user, thereby aiding the user to maintain the proper location and orientation of the irradiating means and measuring means.

27. The method of claim 26 further comprising the step of illuminating the eye at an intensity to cause the pupil to contract thereby maximizing the reflecting area of the iris.

28. The method of claim 26 further comprising the step of providing a visible light pattern indicative of positioning errors and their direction, the light from which being at least partially blocked by the iris when the apparatus is correctly positioned.

29. A method of determining non-invasively and in vivo the concentration of glucose in the aqueous humor of the eye, said method comprising the steps of:

a) irradiating in vivo and non-invasively the eye with near-infrared energy having at least several wavelengths, the energy being reflected from at least one structure within the anterior portion of the eye and reemerging after having undergone differential absorption within the aqueous humor of at least some of said wavelengths characteristic of glucose and other constituents of the eye and their respective unknown concentrations;

b) measuring the spectral intensity of the near-infrared energy reemerging from the eye and producing electrical signals representative of said measured intensity; and

c) calculating the unknown concentration of glucose in the aqueous humor of the eye from variations of said measured intensity signals.

30. The method of claim 29 further including the step of deriving the concentration of blood glucose from the calculated concentration of glucose in the aqueous humor of the eye.

BACKGROUND OF THE INVENTION

a) Field of the Invention

The present invention relates to instruments and methods for the spectrophotometric determination of glucose in the aqueous humor of the eye and the estimation of the level of glucose in the blood based on the values thus obtained.

b) Background Art

An important aspect in the treatment of diabetes is the frequent determination of the blood glucose level of the patient so as to manage food intake and the dosage and timing of insulin injections. Presently, blood glucose analyzers for home use by the patient require lancing of the finger to obtain a drop of blood. The blood is placed on a strip containing reagents which react with glucose to form a chromophor which is then read by a reflectance colorimeter within the analyzer. This procedure is painful and it may result in infections which are particularly hazardous to diabetic persons. In addition, the annual cost of reagent strips can range from several hundred to over one thousand dollars per year per patient.

Non-invasive in vivo determination of blood constituents by near-infrared spectroscopy was first applied to oximetry, the determination of the oxygen content of the blood based on the spectral characteristics of hemoglobin and oxyhemoglobin. Wood (U.S. Pat No. 2,706,927) described a method using two wavelengths of light. Shaw (U.S. Pat. No. 3,638,640) improved this procedure by using more wavelengths of light. This technique was made significantly more practical by use of the modulation caused by the pulse as invented in 1972 by Aoyagi (Japanese Application 947714, April 1979). Improvements were described by Nielsen (U.S. Pat No. 4,167,331) and Flower (U.S. Pat. No. 4,863,265). This pulse oximetry technique is in routine clinical use. Jobsis (U.S. Pat. No. 4,223,680), Chance, Ferrari, Hazeki, Seiyama, Tamura, Takada and coworkers have applied spectrophotometric techniques to the in vivo determination of oxygen in the brain and other tissues. Research in this area continues. Relevant publications include: Chance Bet al., "Comparison of time-resolved and -unresolved measurements of deoxyhemoglobin in brain", Proc. Natl. Acad. Sci. USA 85: 4971-4975; Ferrari Met al., "Continuous non-invasive monitoring of human brain by near-infrared spectroscopy", Adv Exp Med Biol 191:873-882 (1985); Hazeki O et al., "Near-infrared spectrophotometric monitoring of haemoglobin and cytochrome a,a.sub.3 in situ" Adv Exp Med Biol 215: 283-289 (1987); Seiyama A et al., "Simultaneous Measurement of Haemoglobin oxygenation of brain and skeletal muscle of rat in vivo by near-infrared spectrophotometry", Adv Exp Med Biol 215: 291-295 (1987); Tamura Met al., "Spectroscopic characteristics of rat skeletal and cardiac tissues in the visible and near-infrared region", Adv Exp Med Biol 215:297-300 (1987); Takada M et al., "Non-invasive near-infrared measurements of human arm tissues in vivo", Adv Exp Med Biol 215:301-304 (1987); Ferrari M et al., "Determination of cerebral venous hemoglobin saturation by derivative near-infrared spectroscopy" Adv Exp Med Biol 248:47-53 (1989).

Various workers have attempted to use near-infrared spectroscopy for the in vitro or in vivo characterization of tissue for malignancy including Rosenthal (U.S. Pat No. 4,017,192), who suggested in vitro examination, and Stoddart (U.S. Pat. Nos. 4,570,638, 4,725,147, and 4,817,623), who described an in vivo method and apparatus. To date these methods do not appear generally useful.

The use of in vivo spectrophotometric measurements for the non-invasive transcutaneous determination of glucose was described by Dahne and Cross (U.S. Pat. No. 4,655,225) using typically two wavelengths of near-infrared light in the range from 1000 to 2700 nanometers. Investigations by Peura and Mendelson were reported by Schrady in February 1985. Schrady N, "The view from a distance; advances in optics and electronics are allowing physicians to glean diagnostic information without drawing blood", Forbes 135 (2): 142 (1985). Schmidtke (DE 3541165, EP 226822) described a three-wavelength device for measurement of glucose through the ear lobe using interference filters at 805, 1300, and 1600 nanometer wavelengths and optical modulation at different frequencies to separate the information. Rosenthal (U.S. Pat. No. 5,028,787) describes a system for in vivo measurement of glucose in blood using transmission or interaction at least one pair of wavelengths in the spectral region between 600 and 1100 nanometers. Robinson (U.S. Pat. No. 4,975,581) describes methods and apparatus means for the determination of an analyte in biological fluid samples characterized by the algorithm and mathematical calibration model used to calculate unknown concentrations of the analyte. NASA has supported SBIR Phase 1 and Phase 2 programs in "Non-invasive blood analysis during manned space flight" under contract 90-1-12.02-1545 with Boston Advanced Technologies. To date, while the results are promising, none of these approaches has reached the level of precision and accuracy necessary for effective monitoring of blood glucose levels in vivo, largely due to the interferences from other blood constituents, notably hemoglobin in the 600 to 1100 nanometer region, and from various tissue components. In addition, the pulse and movements by the patient during measurement add temporal variations to the measurements.

March (U.S. Pat. Nos. 3,958,560 and 4,014,321) suggested the measurement of optical rotation to determine the glucose concentration in the aqueous humor of the eye which was then related to the blood glucose level of the patient. However, miniaturization and attachment of the measurement device to the eye in similar fashion to a contact lens proved impractical. However, Reim and March provide evidence that the glucose level in the aqueous humor is related to that in the blood and the lag time between blood glucose changes and aqueous humor concentrations is sufficiently short to allow monitoring of blood glucose via measurements on aqueous humor.

It is, accordingly, an object of the present invention to provide a new and improved apparatus for and method of using near-infrared energy for the determination of glucose concentration in the blood based on measurements made of the aqueous humor of the eye.

SUMMARY OF THE INVENTION

In accordance with one aspect of the present invention, a broad band of near-infrared energy is caused to illuminate the eye, particularly the corneal region, in such a manner that the energy passes through the aqueous humor in the anterior chamber of the eye and is then reflected from the iris. The reflected energy then passes back through the aqueous humor and the cornea and is collected for spectral analysis and detection. The constituents of the cornea, aqueous humor, and iris absorb near-infrared energy at different wavelengths in amounts that are characteristic of the materials and their concentration within the optical path. The electrical signals representative of the reflected optical energy at a multitude of wavelengths are processed using multivariate modeling and calibration techniques to provide for calculation and readout of the estimated blood glucose levels based on the spectral absorption of glucose and of the other interfering substances in the eye and the correlation of the spectral absorption within the eye to blood glucose levels.

Another implementation of the present invention provides that the eye is illuminated by a narrow wavelength band of energy, the center wavelength of which is sequentially varied continuously or in a stepwise manner so that a non-wavelength-specific detection means can provide electrical signals representative of the multitude of wavelengths necessary for determination of glucose as described above.

Yet another implementation of the present invention provides that a broad band of near-infrared energy is spectrally encoded, by means such as an interferometer, a time-variable encoding mask placed in a dispersed spectral image, an acousto-optical filter, the electrical modulation of multiple discrete sources, or other similar techniques known to the art. The multiplicity of encoded narrow wavelength bands are simultaneously used to illuminate the eye. The combined reflected energy is collected and converted to a composite electrical signal representative of the energy at all wavelengths simultaneously. This electrical signal is decoded by means such as the Fourier transform, Hadamard transform, or other techniques related to the original encodement technique to provide information relating to the reflected energy at each of the multiplicity of narrow wavelength bands which comprise the broad band illumination of the eye. These spectral data are used as above to determine blood glucose.

In accordance with another aspect of the present invention, the illumination and detection means are configured and positioned so that the specular reflection of the illumination from the curved anterior surface of the cornea is directed away from the detection means thereby preventing the spectroscopic errors associated with the detection of light which has not undergone absorption by the sample. In addition, the detection means is configured and positioned so that extraneous light from the surrounding environment is substantially blocked so that it does not reach the detection means.

In accordance with another aspect of the present invention, the illuminating energy is modulated optically or electrically and the detection and electrical signal processing means are made responsive only to said modulated signals while discriminating against signals that are unmodulated or those modulated at the frequency of the power line and its harmonics, thereby rejecting constant extraneous illumination such as sunlight and artificial sources which have a constant intensity and/or an intensity component which varies in accordance with the powerline frequency supplying said sources.

In accordance with another aspect of the present invention, the fixation means produce visible light so directed as to provide a fixation point for the user, thereby aiding the user to maintain the proper location and orientation of the apparatus. The intensity of this source is such that it will cause the pupil to contract thereby maximizing the reflecting area of the iris. Additional visual cues for the positioning of the device are provided by incorporation of more visible light sources in a pattern indicative of positioning errors and their direction, the light from which is all or partially blocked by the iris when the unit is correctly positioned. Additional visual indications are provided by blinking the light source at various rates or the use of additional sources arranged in accordance with the principles of this aspect of the invention.

In accordance with another aspect of the present invention, the electrical signals representative of the reflected energy are analyzed by univariate and/or multivariate signal processing techniques to determine whether the user has moved the apparatus, blinked, moved the eye, or otherwise caused changes in the measurement geometry that could cause errors in the glucose determination. The signals are also analyzed to ensure that they conform to the multivariate calibration model. The entire measurement sequence is repeated at a sufficiently high rate so that moderate motions typical of hand-held operation will not cause significant errors. Non-conforming signals are automatically rejected and not included in the signal averaging process. A visual and/or aural indication is provided for the user to indicate that the signals are suitable for processing thereby aiding correct operation by rapid feedback and rein