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Noninvasive in vivo Glucose Sensing Using an Iris Based Technique
Abstract
Physiological glucose monitoring is important aspect in the treatment of individuals afflicted with diabetes mellitus. Although invasive techniques for glucose monitoring are widely available, it would be very beneficial to make such measurements in a noninvasive manner. In this study, a New Zealand White (NZW) rabbit animal model was utilized to evaluate a developed iris-based imaging technique for the in vivo measurement of physiological glucose concentration. The animals were anesthetized with isoflurane and an insulin/dextrose protocol was used to control blood glucose concentration. To further help restrict eye movement, a developed ocular fixation device was used. During the experimental time frame, near infrared illuminated iris images were acquired along with corresponding discrete blood glucose measurements taken with a handheld glucometer. Calibration was performed using an image based Partial Least Squares (PLS) technique. Independent validation was also performed to assess model performance along with Clarke Error Grid Analysis (CEGA). Initial validation results were promising and show that a high percentage of the predicted glucose concentrations are within 20% of the reference values.
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Glucose monitoring technology has been used in the management of diabetes for three decades. Traditional devices use enzymatic methods to measure glucose concentration and provide point sample information. More recently continuous glucose monitoring devices have become available providing more detailed data on glucose excursions. In future applications the continuous glucose sensor may become a critical component of the closed loop insulin delivery system and, as such, must be selective, rapid, predictable and acceptable for continuous patient use. Many potential sensing modalities are being pursued including optical and transdermal techniques. This review aims to summarize existing technology, the methods for assessing glucose sensing devices and provide an overview of emergent sensing modalities.
A potential noninvasive glucose sensing technique was investigated for application towards in vivo glucose monitoring for individuals afflicted with diabetes mellitus. Three dimensional ray tracing simulations using a realistic iris pattern integrated into an advanced human eye model are reported for physiological glucose concentrations ranging between 0 to 500 mg/dL. The anterior chamber of the human eye contains a clear fluid known as the aqueous humor. The optical refractive index of the aqueous humor varies on the order of 1.5x10-4 for a change in glucose concentration of 100 mg/dL. The simulation data was analyzed with a developed multivariate chemometrics procedure that utilizes iris-based images to form a calibration model. Results from these simulations show considerable potential for use of the developed method in the prediction of glucose. For further demonstration, an in vitro eye model was developed to validate the computer based modeling technique. In these experiments, a realistic iris pattern was placed in an analog eye model in which the glucose concentration within the fluid representing the aqueous humor was varied. A series of high resolution digital images were acquired using an optical imaging system. These images were then used to form an in vitro calibration model utilizing the same multivariate chemometric technique demonstrated in the 3-D optical simulations. In general, the developed method exhibits considerable applicability towards its use as an in vivo platform for the noninvasive monitoring of physiological glucose concentration.
We used an optical sensor combined with a Mach-Zehnder interferometric waveguide and optical fibers to measure slight changes of aqueous sugar concentrations. The merits of this sensor are simplicity, reliability, high sensitivity and continuous monitoring. The technique is based on the fact that the refractive index of sugar solution changes with the concentration of sugar. In the experiment, one arm of the interferometer is clad with glue and is thus isolated from the sugar solution. The other one is exposed to the sugar solution. A single mode fiber is directly glued onto the interferometric waveguide, to guide the light into the interferometer. If the concentration of sugar covering the waveguide changes, the phase of propagating light in the exposed arm will be changed, while the phase in the other arm is fixed. Hence the output intensity from the interferometer is directly related to the concentration of the sugar solution. The result of this experiment yields the relation between the sugar concentration and output signal. From 0% to 1% concentration of sugar solution, there is only a 1.410–3 refractive index difference. Two sets of experimental data have been obtained, showing a linear relation between the sugar concentration and the output signal from our sensor. This sensor could be used for continuous monitoring of blood sugar in the human body.
Background:
The ability to measure glucose concentration through noninvasive approaches would impact the treatment of diabetes significantly. Polarization-based optical approaches have received considerable interest because of their potential medical applications. Glucose, a chiral molecule, has the ability to rotate the plane of linearly polarized light, commonly referred to as optical activity, as well as changing the refractive index of the media, which therefore affects the overall scattering coefficient in a given media. The magnitude of each effect is related to the concentration of glucose. Although most previous studies have reported on the use of polarimetry in the aqueous humor of the eye because of its nonscattering nature, one would also expect that glucose concentration could be measured in more turbid media such as tissue through a similar approach. This study investigated how each of these effects is correlated to glucose concentration in a physiological range for highly scattering biological media.
Methods:
A custom-designed imaging polarimeter was used to image highly scattering Intralipid-based media containing different concentrations of glucose. Model formation and glucose prediction were performed through the use of partial least squares (PLS) regression. Further insight into the differences between polarization-based image measurements and encoding of glucose information was provided through the use of principal component analysis (PCA).
Results:
When coupled with PLS regression, in vitro polarization measurements yielded highly correlated glucose predictions in both calibration and independent validation, 0.999 and 0.998, respectively. Through the use of PCA, it appears that the majority of the image-based signal yielding the most significant glucose information is attributable to changes in the overall scattering coefficient due to glucose concentration and, to a lesser degree, effects of optical activity.
Conclusions:
This study showed how polarimetric-based imaging coupled with PLS regression can be used to quantify glucose concentration in highly scattering media. Such methods may potentially be able to extend the use of noninvasive in vivo polarimetric measurements, normally acquired in the anterior chamber of the eye, to other preferred sensing sites such as the skin.
In the recent past, several noninvasive optically based methods have been proposed for physiologic glucose sensing. One proposed optical sensing site has been the eye, which, due to its unique optical properties, can be considered as a transparent optical window into the body. In particular, the aqueous humor within the anterior chamber of the eye has been shown to contain glucose levels correlated to those of blood. Concern, however, has been expressed that using the aqueous humor solution as a measure of blood glucose may be problematic due to the potential transport time delay between the blood and the aqueous humor glucose concentrations. This investigation was performed to measure the transport time delay in a rabbit model. The time delay between the blood and aqueous humor glucose concentrations was measured invasively in five New Zealand White rabbits over a series of weeks. An anesthesia protocol containing the drug Xylazine was used to elevate the blood glucose levels to a level commonly seen in diabetic patients. The difference between the glucose peak location times occurring in the blood and aqueous humor glucose response was measured and defined as the transport time delay. The average transport time lag was measured to be under 5 min. This measured time delay indicates that, indeed, the eye could potentially be used as a sensing site for indirect blood glucose measurements and may eventually aid the development of a noninvasive glucose sensor due to its unique optical properties compared to other biological tissues.