Optical method and device for determining blood glucose levels

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FIELD OF THE INVENTION

This invention relates generally to the field of optics and more specifically to a method and device for analyzing a patient's perception of a changing light pattern and relating such to the patient's blood glucose level.

BACKGROUND OF THE INVENTION

More than ten million people in the United States of America suffer from diabetes, a deficiency in the body's ability to regulate blood glucose levels. Individuals afflicted with the disease must control their blood glucose levels by measuring their blood glucose levels as frequently as possible and planning accordingly their food intake, level of physical activity and insulin dosage. The measurement of blood glucose levels is done using one of several available invasive techniques.

Invasive techniques require withdrawal of a blood sample from the patient each time an analysis is to be performed. An accurate laboratory blood analysis requires withdrawing from 5 to 10 ml of blood and analyzing it using a laboratory instrument designed for performing such a biochemical analysis. However, the results of the test often are not available for several hours, and sometimes days. In addition, the instruments necessary to perform such an analysis are expensive and require that the blood samples be taken and analyzed by trained technicians.

Another invasive technique, referred to as a "finger poke" or a "finger stick" uses an integrated, self-contained instrument that evaluates a much smaller blood sample (approximately 0.25 ml). The small blood sample is obtained by puncturing a finger with a small lancet. The sample is then placed on a chemically treated carrier and inserted into the instrument. The finger poke devices normally provide the glucose concentration results in a few moments. However, they are still quite costly for private use.

More recently, portable finger poke instruments have become available which require the use of single use, disposable, chemically treated carrier "strips". Although the portable instruments have a relatively low cost (about $100 to $300), cumulative cost to diabetics for the normal supply of disposable carrier "strips" is considerable.

Invasive techniques for glucose analysis are problematic and suffer from poor compliance. Although diabetics can forestall the debilitating and often fatal complications of diabetes by frequent monitoring and control, only a small fraction of diabetics monitor regularly their glucose levels. Diabetics find the current invasive methods of blood glucose monitoring painful, inconvenient and costly. To encourage frequent monitoring and control there is a clear need for a glucose monitor that requires no blood samples, is easy and convenient to use, is portable, and costs less than current methods.

Non-invasive methods for measuring blood glucose have been described. However, to date none of these techniques has resulted in a commercially useful instrument. The non-invasive monitoring methods are roughly divided into measurements based on either (1) the intensity of light being transmitted through or reflected from the tissue ("intensity-sensitive" measurements), (2) the phase shift of modulated light transmitted through the tissue ("phase-sensitive" measurement) or (3) devices which use reverse iontophoretic means to remove substances through the skin as per U.S. Pat. No. 5,279,543 issued Jan. 18, 1994.

When light is transmitted through perfused tissue in vivo, e.g., through a patient's finger, it is differently absorbed by the various components illuminated, namely blood, with its many constituent parts, tissue (including protein, fat, water, cholesterol, etc.), cartilage, and bone. Each component has a specific absorption spectrum, which indicates the absorption at each wavelength of light.

The known intensity sensing methods for measuring the level of a blood constituent, including glucose, are based on measuring an absorption spectrum for blood perfused tissue at two or more different wavelengths, and subtracting therefrom the statistical absorption spectra for each of the various components, except for the one component being measured. It is assumed that after such subtraction, the remainder is the spectrum of the constituent to be measured.

Rosenthal, et al., U.S. Pat. No. 5,086,229 refers to such a non-invasive, near-infrared quantitative analysis instrument for measuring blood glucose. The instrument contains a plurality of near-infrared laser sources having different wavelengths of emission and one or a plurality of photodetectors. A blood-containing body part, e.g., a finger, is placed between the laser sources and photodetectors. The light sources illuminate the body part and the wavelengths transmitted through the body part are detected. The absorption spectra obtained from the photodetector signals are compared with individual statistical absorption spectra of each constituent, which are stored in the memory of the instrument. A glucose level is derived from the comparison.

The non-invasive phase sensitive measurement methods possess significantly higher sensitivity and a much higher signal-to-noise ratio than intensity-measurement methods. The higher sensitivity is the consequence of the noise sources affecting the amplitude, but not the phase, of a signal.

In phase sensitive techniques, an instrument compares a known reference signal, e.g., a sine wave, with a measurement signal that has been passed through the tissue. The measurement signal will have a phase shift relative to the reference signal, and concentrations of blood constituents may be obtained from a measurement of the phase shift.

Cote, et al., "Noninvasive Optical Polarimetric Glucose Sensing Using A True Phase Measurement Technique," IEEE Transactions of Biomedical Engineering, Vol. 39, No. 7, July 1992, pp. 752-756, refers to passing linearly-polarized light through the anterior chamber of an excised human eye and determining the glucose level of the aqueous eye humor based on the phase shift between the reference signal and the measurement signal that was affected by glucose. A helium-neon laser beam, coupled through a rotating linear polarizer along with two stationary linear polarizers and two detectors, is used to produce reference and measurement signal outputs. The amplitudes of these outputs varied sinusoidally with a frequency twice that of the angular velocity of the rotating polarizer. The phase difference of the outputs would be proportional to the polarization rotation introduced in the measurement beam by the anterior chamber of the eye.

Due to problems with both types of systems there is a continuing need for improved non-invasive analytical instruments and methods that would provide essentially the same accuracy as conventional invasive blood glucose tests. There also is a need for non-invasive, low-cost methods and instruments for the measurement of glucose levels in diabetic patients. There also is a need for a durable, cost-effective, and environmentally conscious nondisposable apparatus for measuring blood glucose. In view of such the present invention now provides an apparatus for non-invasive measurement of blood glucose concentration.

SUMMARY OF THE INVENTION

A human subject is presented with a changing light stimulus or pattern in which one or several parameters, for example the luminance, color, flicker frequency, spatial contrast, speed, etc., of a portion of the pattern or of the whole of the pattern, gradually change in a manner which stimulates a first retinal system (e.g., the P-system) and a second retinal system (e.g., the M-system) in a continuously changing ratio. The stimulus or pattern is observed until the person observing the pattern subjectively notes a specific change in the appearance of the light pattern, for example the appearance of a specific color in the light pattern, or the reversal in the direction of rotation of the light pattern. The specific change is associated with a specific ratio of stimulation of the M- and P-systems, for example the point of balanced stimulation of the two systems, or M-P crossover point. The value of at least one of the variable light stimulus parameters at the moment of occurrence of the specific change in appearance of the light stimulus, can be calibrated to the subject's blood glucose level via prior measurements of the subject's blood glucose level. Such value of the variable stimulus parameter when the specific change in the stimulus appearance occurs, will shift for any given person as the glucose level of the person changes, because the sensitivity of the two retinal systems change relative to each other in response to changes in blood glucose level.

In one preferred embodiment, a series of images resembling windmill wheels are presented to a person in a manner which causes the person to perceive rotation of the wheel. A gradual change in the brightness or color of portions of the images or their background is then effected in such a manner that the series of images stimulates one retinal system (M or P) over time at a certain rate, and the other retinal system (P or M) at a different rate. The different manner in which the M- and P-systems respond to changes in the parameters of a light pattern make it possible to stimulate the M- and P-systems at different rates by varying continuously one or several parameters in the light pattern. The resultant ratio of stimulation of the two systems changes gradually over time. This gradual change in the ratio of stimulation of the two retinal systems is continued until the patient notes a reversal in the direction of apparent rotation of the wheel--rotation reversal indicating a balanced stimulation of the M- and P-systems, or M-P crossover point. A change in blood glucose level affects the retinal systems in a manner which causes the M-P crossover point to shift in a predictable and consistent manner, because the sensitivity of each of the two retinal systems is affected differently relative to each other by changing blood glucose levels. The value of the variable parameter or parameters of the light stimulus at the point when the person notices the rotation reversal is directly related to blood glucose levels. Thus, by relying on the differential response of the M-system and the P-system to changes in certain types of light patterns, and on the differential change in sensitivity of the M-system and the P-system with blood glucose levels, the device and method provide an accurate, convenient, non-invasive means of measuring a patient's blood glucose level.

An object of the invention is to provide a non-invasive optical means of determining a patient's blood glucose level.

Another object is to provide the non-invasive means for determining glucose levels by using images or light patterns which provide visual stimulation to the retina and determining with such images or light patterns changes that take place in a patient's retina in response to changes in blood glucose levels.

Another object of the invention is to provide a device which creates a changing light stimulus which when observed reaches an M-P crossover point which is related to the blood glucose level of the observer.

Another object is to provide such a device which gradually stimulates one retinal system more and more and another retinal system less and less and provides for an actuation means which upon actuation records a point which can be related to the relative stimulation of each system which information can be related to the blood glucose level of the patient.

Yet another object of the invention is to provide a device which provides a light stimulus with an observable M-P crossover point which device is calibrated with an established relationship between known blood glucose levels and measured M-P crossover points.

A feature of the invention is that it uses changing light patterns.

An advantage of the invention is that it is a non-invasive method of determining a blood glucose level.

Another feature of the invention is that it capitalizes on the different sensitivities of the M-system and the P-system to determine information on blood glucose level.

Another advantage is that the method can be quickly carried out in only a few seconds.

Another advantage is that the device for measuring glucose levels via optical means can be inexpensively manufactured.

Another advantage of the device of the invention is that the patient can reuse the device a plurality of times, i.e., it is not a one use disposable item and does require the use of any disposable components.

Still another advantage is that the device is small (less than 10 cm in any dimension) light weight (less than 0.5 kg) and thus may be conveniently carried and used by an individual on an out-patient basis.

These and other objects, advantages and features of the present invention will become apparent to those persons skilled in the art upon reading the details of the structure, methodology and usage as more fully set forth below with reference being made to the accompanying figures forming a part hereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph which conceptually shows the relative sensitivities of the M- and P-retinal systems at different glucose levels;

FIG. 2 is a schematic block diagram of an aspect of the invention;

FIG. 3 is a graph which conceptually shows how the M-P crossover point changes as blood glucose level changes;

FIG. 4 is a schematic view of the arrangement of components and the viewer being tested in a particular embodiment of the invention;

FIG. 5 is a graph relating flicker frequency to time;

FIG. 6 is a graph relating glucose level to time;

FIG. 7 is a graph relating glucose level to time;

FIG. 8 is a graph relating glucose level to time;

FIG. 9 is a graph relating glucose level to time;

FIG. 10 is a graph relating critical flicker period to time;

FIG. 11 is a black and white schematic view of a windmill light stimulus in a first position;

FIG. 12 is a black and white schematic view of a windmill light stimulus in a second position;

FIG. 13 is a graph relating background luminance at the point of rotation reversal of the windmill light stimulus to time;

FIG. 14 shows an embodiment of the device;

FIG. 15 is a schematic block diagram showing principal functional sections of the device of FIG. 14;

FIG. 16 is a schematic flow diagram showing steps of a diagnostic sequence; and

FIG. 17 is a graph demonstrating how reaction time is compensated for.

DETAILED DESCRIPTION OF THE INVENTION

Before the present optical method and device for determining blood glucose levels is described, it is to be understood that this invention is not limited to the particular process steps, light changing, light stimulus or other steps and components described as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting since the scope of the present invention will be limited only by the appended claims.

It must be noted that as used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural reference unless the context clearly dictates. Thus, for example, reference to "a changing light stimulus" refers to one or more changing light stimuli, reference to "an actuation means" refers to one or more means and so forth.

Unless defined otherwise all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned hereunder are incorporated herein by reference.

The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the invention claimed herein is not entitled to antedate such publications by virtue of prior invention.

Definitions

The term "appearance of colors" is used to describe a subjective visual effect occurring at a specific frequency when the retina is stimulated with a flickered light of variable frequency. For example, the appearance of colors can consist of pink and green irregular patches that appear to radiate from the point of fixation.

The term "cessation of radial movement" is used to describe a subjective visual effect occurring at a specific frequency when the retina is stimulated with a flickered light of variable frequency. For example, at lower frequencies, faint shadows like concentric ripples in water radiate from the point of fixation towards the periphery, while at higher frequencies, the shadows travel in the opposite direction. At an intermediate frequency, the radial movement of the shadows ceases momentarily before changing direction; this is the frequency of cessation of radial movement and is an example of a subjective visual effect occurring during the observation of a changing light pattern.

The term "changing light pattern" is intended to mean a light pattern that changes over time with respect to one or several of its defining parameters, for example its luminance, color, shape, size or rate of flicker.

The term "changing parameter" shall mean any parameter that changes during the presentation of a light pattern, in order to provide a changing stimulation to the observer's retina. For example, a changing parameter in the windmill light pattern may be the luminance of the background, which could increase gradually. In a flickered stimulus, the flicker frequency may increase, or the length of the ON periods may increase over time.

The term "continuously increasing ratio" is used to describe the ratio of stimulation of one retinal system over the other, when such ratio increases continuously. Thus, if the sensitivity of the M- and P-systems change as shown in FIG. 1, and if the light stimulus is assumed to change from left to right along the horizontal axis, the ratio of M to P stimulation in FIG. 1 increases continuously from left to right, starting with a value of less than 1 on the left end of the diagram, reaching a value of 1 at the M-P crossover point, and continuing to increase to values greater than 1 towards the right side of the diagram.

The term "critical parameter value" is used to describe the value of a variable parameter in a changing light pattern, at the point when the subject notices the subjective visual effect.

The term "grid pattern" is used to describe a subjective visual effect occurring at a specific frequency when the retina is stimulated with a flickered light of variable frequency. The effect consists of a regular pattern, which some observers describe as a fine square grid, and others as a fine honeycomb pattern.

The terms "light pattern", "light stimulus" and the like are used interchangeably herein and are intended to mean any arrangement of light-emitting surfaces that can be used to stimulate the retina. A light pattern can be specified by three kinds of properties: spectral properties (the color of each component part), spatial properties (the size, shape and location of each part), and temporal properties (how each part changes with time). Examples of light patterns are a flickering light or a sequence of windmill images that appear to rotate. A light pattern can be produced with a variety of light sources, such as a CRT screen, an LCD screen, LEDs, fluorescent or incandescent sources, arc or gas discharge lamps, flash tubes, or natural sun light. In order to stimulate the retina with a light pattern the observer may look at the actual light source or the observer may look at an object that in itself is not light-emitting, but receives the light from a light source and re-directs this light to the eye of the observer by either reflection, scatter, diffusion or refraction. Appropriate filters and time-control devices can be used to give the desired spectral and temporal properties to the light pattern.

The term "light pattern parameters" is intended to mean the set of parameters that define a light pattern at one moment in time. Light pattern parameters define the light pattern along three dimensions: spectral parameters, spatial parameters and temporal parameters. Examples of light pattern parameters are color, luminance, size, and rate of flicker.

The term "luminance" shall mean the quantitative measure of brightness of a light source or an illuminated surface, formally defined as luminous flux per unit solid angle emitted per unit projected area of surface.

The terms "M-retinal system", "M-system", "P-retinal system" and "P-system" are used herein to describe the two complementary components of the visual system, presently regarded in vision science as the main channels for processing visual information. The M- and P-retinal systems originate at the ganglion cell layer of the retina and connect respectively to the magnocellular and parvocellular layers of the lateral geniculate nucleus in the brain. The M- and P-systems differ in their color selectivity, contrast sensitivity, temporal properties, spatial resolution and sensitivity to changes in blood glucose levels. The two systems are compared in Tables 1 and 2. It is understood that the differences with respect to some parameters may be gradual even though Tables 1 and 2 appear to imply a discrete and complete separation of sensitivities. The present invention makes use of the differences in the M- and P-systems to stimulate the two systems selectively and to gradually shift the stimulation from predominantly M to predominantly P or vice versa.

The terms "M-P crossover point", "crossover point" and the like are used interchangeably herein to define the point where the M- and P-systems are stimulated substantially equally. The M-P crossover point can be reached by changing the light pattern gradually in such a manner th