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Noninvasive Continuous Monitoring of Tear Glucose Using Glucose-Sensing Contact Lenses

Ascaso, Francisco J.; Huerva, Valentín

doi: 10.1097/OPX.0000000000000698
Biosensing

The incidence of diabetes mellitus is dramatically increasing in the developed countries. Tight control of blood glucose concentration is crucial to diabetic patients to prevent microvascular complications. Self-monitoring of blood glucose is widely used for controlling blood glucose levels and usually performed by an invasive test using a portable glucometer. Many technologies have been developed over the past decades with the purpose of obtaining a continuous physiological glycemic monitoring. A contact lens is the ideal vehicle for continuous tear glucose monitoring of glucose concentration in tear film. There are several research groups that are working in the development of contact lenses with embedded biosensors for continuously and noninvasively monitoring tear glucose levels. Although numerous aspects must be improved, contact lens technology is one step closer to helping diabetic subjects better manage their condition, and these contact lenses will be able to measure the level of glucose in the wearer’s tears and communicate the information to a mobile phone or computer. This article reviews studies on ocular glucose and its monitoring methods as well as the attempts to continuously monitor the concentration of tear glucose by using contact lens–based sensors.

*MD, PhD

Department of Ophthalmology, Hospital Clínico Universitario “Lozano Blesa”, Zaragoza, Spain (FJA); School of Medicine, University of Zaragoza, Zaragoza, Spain (FJA); Instituto de Investigación Sanitaria de Aragón, Zaragoza, Spain (FJA); Department of Ophthalmology, University Hospital “Arnau de Vilanova”, Lleida, Spain (VH); and IRB Lleida, Lleida, Spain (VH).

Valentín Huerva Department of Ophthalmology University Hospital Arnau de Vilanova Avda Alcalde Rovira Roure 80 25198 Lleida Spain e-mail: vhuerva@gmail.com

The incidence of diabetes mellitus, a chronic systemic disease characterized by raised blood glucose levels, is dramatically increasing in the developed countries. In 2013, the prevalence of diabetes across the world ranged from 5.7% in the African region to 11.0% in the North American and Caribbean region. That year, 382 million adults had diabetes; this number is expected to rise to 592 million by 2035. Most people with diabetes live in low- and middle-income countries and these will experience the greatest increase in cases of diabetes over the next 22 years.1 Early diagnosis and tight control of blood glucose concentration are crucial to patients to prevent microvascular complications such as atherosclerosis, coronary artery disease, stroke, peripheral vascular disease, kidney failure, and blindness.2 Self-monitoring of blood glucose is widely used for controlling blood glucose levels and usually performed by an invasive test using a portable glucometer.3 Currently, millions of diabetic subjects have to prick their finger for a drop of blood several times a day, about 1800 times per year, to check glucose levels.4 However, the glucose meter provides only a temporal value, the pain of the finger-stick blood sample severely reduces patient compliance with frequent glucose measurement, and cases of blood-borne infection have been reported with these invasive glucose sensors.5 Therefore, this method is not ideal, and real-time painless sensing devices for continuous noninvasive (or minimally invasive) glucose monitoring could increase safety and convenience of testing, having considerable impact in public health.

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Monitoring Glucose Levels in Diabetic Patients

Since the first glucose sensor was designed by Clark and Lyons6 in 1962, several technologies have been developed over the past decades. Thus, with the purpose of obtaining a continuous physiological glycemic control, several implantable biosensors used in subcutaneous tissue and vessels have been developed for in situ monitoring of blood glucose.4,7,8 A blood glucose meter only provides a brief “snapshot” of glucose level at a single moment in time. A continuous glucose monitoring device can provide valuable information at crucial points during the day, including before and during exercise, before driving, before test/examination taking, and in the middle of the night. Moreover, continuous glucose monitoring is important in diabetic management, as hypoglycemia is a common and life-threatening issue in certain patients. Although they provide accurate blood glucose concentration, the implant process requires surgery and can be complicated with obstructions.9

Because of this, noninvasive techniques have received significant research interest, with typical noninvasive biosensors being based on many different approaches, including iontophoretic extraction of glucose through the skin,10 visible11 or near-infrared (NIR) spectroscopy,12 Raman spectroscopy in aqueous humor,13 polarimetry,14,15 photo-acoustic probes,16 surface plasmon resonance,17 and fluorescence methods.18–20 Nevertheless, results from these innovative devices need to be calibrated frequently (e.g., twice a day) against direct blood glucose measurements; that is, they cannot replace the direct measure of a blood glucose sensor.4 Consequently, the challenge of preparing accurate enough sensors to biomonitor easily and painlessly blood glucose level remains to be solved.

A noninvasive diagnostic alternative to finger-stick glucose testing would be to measure indirectly the concentration of glucose in physiological and accessible body fluids, such as urine, tears, mucus, sweat, saliva, and so on. The main disadvantage of this method is its intermittent nature, which means that it is not possible for continuous monitoring. However, several sensor designs could allow continuous monitoring in the tear fluid. Tears are more accessible than other body fluids, such as blood or interstitial fluid. They are also more continuously obtainable and less susceptible to dilution than urine.5 Since tear glucose was studied for the first time in 1930s,21 the relationship between tear glucose and blood glucose has been studied by different methods in both human and animals, revealing that tear glucose is usually higher in diabetic patients than in healthy subjects.22–24 In fact, it has been demonstrated that blood glucose is about two times higher in diabetic patients than in nondiabetic patients, whereas tear glucose is about five times higher in diabetic patients than in nondiabetic patients.25 However, although several authors have reported a good correlation between tear glucose and blood glucose, others talk about the glucose levels in tears being below detection.22,26 These discrepancies are probably attributed to the different tear collection methods, for example, filter paper or microcapillary. This could also be secondary to differences in techniques used to quantify tear glucose. Furthermore, it is possible that glucose is not expressed in the tear film of certain patients.

The development of an in situ ocular glucose sensor for diabetes control has certain limitations. On the one hand, it takes several minutes to collect enough tear sample by using glass capillaries.27 On the other hand, the glucose levels in the tears are lower than those in blood.28 In fact, only a few methods have been designed to test tear glucose. In 2010, a polarimetric glucose sensor was developed for monitoring ocular glucose.29 Nevertheless, the time lag between changes to blood glucose and aqueous humor glucose levels was an average of 5 minutes.5 Other approaches are related to contact lens–based glucose sensors, which have great potential to achieve a continuous and noninvasive diabetes control through a portable and disposable device. Moreover, hydrogel-based soft contact lenses are approved as safe daily wear lenses in diabetes patients.30

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Contact Lens Biosensor for Diabetes Mellitus

Contact lenses have applications beyond being an alternative to glasses to correct refractive errors. March et al.31 first introduced the idea of a contact lens to monitor glucose in the 1980s. In recent years, various noninvasive and minimally invasive technologies have been proposed in the academic literature to monitor blood glucose levels by determining glucose concentrations in an ocular fluid, such as tear.23,24,32–35 Furthermore, Table 1 shows the patent literature on tear film glucose level continuous monitoring devices. It includes several electrochemical sensors, which are all contact lens based. There are at least three research groups who are working with sensors integrated into contact lenses for continuously and noninvasively monitoring tear glucose levels.23,32,33 The development of contact lenses with embedded sensors includes two general methods in the determination technique: spectral determination, using fluorescence-based techniques24 or glucose-sensitive hydrogels embedded with photonic crystals,34,35 and electrochemical determination.9

TABLE 1

TABLE 1

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Tear Glucose Monitoring by Spectral Determination Method

Regarding the first method, March et al.31 were the first authors to expand the idea to ocular spectroscopy, the measurement of a metabolite in the eye with a light beam. They prepared a glucose-sensitive contact lens by immobilizing two types of fluorescent indicators in the lens material as it is polymerized.36 In the presence of glucose, the indicators dissociated and fluorescence was detected. The signal could be read with the aid of an illumination/recording unit held in front of the eye.24 Other studies have used this competitive-binding glucose assay method based on fluorescence quenching of ligands to monitor glucose.37 Daily-wear disposable contact lenses with no embedded substances have been shown to be safe for patients with diabetes.30 Domschke38 provided the first description of a successful initial 30-minute clinical trial of a daily-wear disposable holographic contact lens glucose sensor for the noninvasive home monitoring of blood glucose. Alexeev et al.32 developed another similar system based on embedding photonic crystals in a hydrogel patch, creating a holographic hydrogel. When the hydrogel is illuminated, the wavelength of the refracted light varies according to the glucose level. If a hydrogel material was incorporated in a contact lens, the wearer could read out the glucose concentration by matching the color of the patch to a graduated scale.24

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Tear Glucose Monitoring by Electrochemical Determination Method

In relation to the abovementioned second method, one of the first reports of a flexible electrochemical sensor used for monitoring glucose level in human tears, saliva, and sweat was published in 1995 by Mitsubayashi et al.39 The device was based on immobilized glucose oxidase (GOD). This progress was followed by numerous publications dedicated to the development of biosensors suitable for measurements in situ while being selective and sensitive toward glucose.9,24,40–44 Thus, Yao et al.24 proposed the possibility of in situ human health monitoring simply by wearing a contact lens. These authors reported the design, construction, and testing of a contact lens with an integrated amperometric glucose biosensor (Fig. 1). It was fabricated by creating microstructures on a polymer substrate, which was subsequently shaped into the contact lens. Glucose oxidase was immobilized by applying titania sol-gel film and Nafion was used to decrease several potential interferences (lactate, ascorbic acid, and urea) present in the tear liquid. The sensor exhibited a rapid response (20 seconds), a high sensitivity (240 μA cm−2 mM−1), and a good repeatability, in the range of low concentrations of glucose found in the tear film. It showed good linearity for the typical range of glucose concentrations in the tear film (0.1 to 0.6 mM) and acceptable accuracy in the presence of interfering agents. The biosensor was able to attain a minimum detection of less than 0.01 mM glucose. In any case, a noninvasive and continuous glucose monitor suitable for such body-area network–related technologies was strongly requested. In this sense, blood glucose assessment with a body-area network–friendly device in mind, Chu et al.9 designed and fabricated a contact lens biosensor that continuously measured in situ tear glucose (Fig. 2). The final goal of their device included integration of a power source, a body-wired communication transmitter, an electrical circuit, and a sensing probe. The biosensor material was fabricated by using micro-electro-mechanical systems technique to form GOD electrodes on the peripheral surface of a polydimethyl siloxane (PDMS) contact lens (Fig. 3). Owing to the wearable structure of the sensor like a contact lens, noninvasive ocular biomonitoring was established with minimum irritation. Because of in vitro characterization, the sensor had a fast response to glucose and appropriate calibration range (0.03 to 5.0 mM), which included the reported tear glucose concentrations. In the preclinical animal model, and in accordance with the oral glucose tolerance test, the tear glucose changed with a delay of 10 minutes from the blood glucose level. In conclusion, the electrochemical approach consists as an electrochemical biosensor on a flat plastic support, either by microfabrication methods42 or by screen printing techniques.43 Because these biodevices are flexible, they could be either attached onto the eye directly42 or rolled up and inserted into the tear canal.43 Both sensors have been demonstrated to have enough sensitivity for detecting tear glucose concentration. Nevertheless, their accuracy has not been validated and certain electroactive species present in tear fluid (mainly ascorbic acid) could interfere.

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

FIGURE 3

FIGURE 3

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Possibilities of Glucose-Sensing Contact Lenses

A contact lens is the ideal vehicle for continuous tear glucose monitoring because the biosensor is naturally in contact with tear film, either normal secretion or blinking.24 Besides improvements in microelectronics fabrication,45 as we described above, integration of a glucose biosensor into a contact lens has recently been made by several research groups that have designed high-performance bionic contact lenses for ocular glucose monitoring.9,24,44 With different types of contact lenses, including integrated glucose sensors already fabricated, functional and practical bionic contact lenses could potentially be realized in the near future (Fig. 4). In fact, not only have glucose biosensors been incorporated into contact lenses but also simple single-pixel displays.46 The polymerized crystalline colloidal array (PCCA), incorporated into contact lens, symbolizes one of the most promising materials for noninvasive monitoring of tear glucose. Nevertheless, low sensitivity and slow time response of the PCCA reported in previous articles33 have limited its clinical utility. Because of this, in 2013, Hu et al.47 designed a new PCCA, denoted as NIR-PCCA, comprising a crystalline colloidal array of glucose-responsive submicrometered microgels embedded in a slightly positive charged hydrogel matrix (Fig. 5). This biosensor can reflect NIR light, whose intensity (at 1722 nm) would decrease with increasing tear glucose profile over the physiologically relevant range. The lowest glucose level reliably detectable was as low as approximately 6.1 μg/dL (0.33 mM). The characteristic response time τ sensing was 22.1 ± 0.2 seconds when adding glucose to 7.5 mg/dL, and the higher the glucose profile is, the faster the time response. Such a rationally designed NIR-PCCA is well suited for ratiometric NIR sensing of tear glucose under physiological conditions, thereby likely to bring this promising glucose-sensing material to the forefront of analytical devices for diabetes.

FIGURE 4

FIGURE 4

FIGURE 5

FIGURE 5

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Limitations of Glucose-Sensing Contact Lenses

Despite the exciting design, it is difficult to measure glucose concentration in tears, because the amount of glucose present is very low: 0 to 64.8 mg/dL (3.59 mM) in healthy control subjects and may be as high as 84.6 mg/dL (4.69 mM) for diabetic subjects, and the tear glucose levels measured appear to be varied by the volume of the aqueous tear fraction collected.26 To achieve high-accurate measurement, the biosensor should be highly accessible by tear glucose, while having a minimal stimulation, which may decrease reflex tearing. Moreover, there is not much information on whether tear glucose levels vary from day to day, or are stable, as happens in blood. This brings up the issue of whether such lenses need to be calibrated every day and/or how often. Finally, hypoglycemia, which can be a severe and life-threatening aspect of diabetic management, often during sleep; a discussion of setting thresholds and alarms in extended-wear contact lenses; and the suitability of extended-wear contact lenses for diabetic subjects should be considered. These aspects are far from being resolved. Much larger studies are needed, which will be critical for regulatory approval and, indeed, the practicality of such a device.

One additional problem for these types of biodevices is the implementation of a suitable power source.48 Although integration with inductive links or radio-frequency circuits has been proposed, these solutions are not ideal and can be rather complicated, requiring inconvenient equipment. Integration of a biofuel cell (BFC) into the bionic contact lens could be an alternative power source.48 Thus, enzyme catalysts have been used to convert the chemical energy from biofuel (glucose) and biooxidant (oxygen) available in tear film into electrical energy.49,50 Biofuel cells appear to be a very attractive alternative power source for bionic contact lenses, because miniature devices can potentially be produced at a low cost and without complicated designs, especially when using enzymes immobilized directly on the electrode surfaces without using any mediators.50 For a glucose-sensing biodevice, use of glucose as a power source would be very problematic. In this sense, a more suitable fuel source present in tear fluid should be used. Thus, to avoid the oxidization of the glucose present in human lachrymal liquid, Falk et al.48 have designed a miniature membrane-less BFC using ascorbate instead of glucose to generate electrical power (Fig. 6). The electrical power production should thereby not alter the glucose level and influence the sensor performance. By means of a miniature membrane-less ascorbate/oxygen BFC, they have demonstrated that enough electrical power can be produced from human basal tears, without influencing the glucose profile of the lachrymal film. Considering the stability and power output of the BFC along with recent advances in modern ultralow power electronics and contact lens–based glucose biosensors, the BFC could be used as part of the design of bionic contact lenses and allow self-powered, noninvasive, continuous glucose monitoring to be realized.48 These biodevices hold great promise in the future as an aid for diabetic subjects and could help improve public health as well as reduce medical costs. Fabrication of BFCs incorporated into suitable flexible biocompatible polymeric materials is currently an ongoing investigation.

FIGURE 6

FIGURE 6

Although contact lens technology is one step closer to helping diabetic subjects better manage their condition, so far, practical applications have been slow to become real. Undoubtedly, it is difficult to solve some functional problems. Thus, these contact lenses should be comfortable to wear to avoid their impact on contact lens discomfort. Therefore, this aspect will be critical to determine whether such a lens would be wearable. Otherwise, vision will be impaired, making such a device cumbersome. Nevertheless, at the time of writing this article, an agreement between the Google research division and the Alcon eye care unit of the Swiss pharmaceutical company Novartis has been announced.51 They will license a smart lens technology for continuously measuring tear glucose levels in the diabetic patient by using a tiny wireless chip and miniaturized glucose sensor that are embedded between two layers of soft contact lens material. The lenses themselves are outfitted with tiny sensors and microchips (Fig. 7). According to the manufacturer, they will be so small they look like bits of glitter, whereas the embedded antenna will be thinner than a human hair. These contact lenses will be able to measure the level of glucose in the wearer’s tears and communicate the information to a mobile phone or computer.

FIGURE 7

FIGURE 7

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CONCLUSIONS

In conclusion, it is clear that testing ocular glucose has great potential for noninvasive diagnosis of diabetes mellitus. Furthermore, monitoring glucose levels through the smart contact lenses could prove to be easier and more comprehensive than current techniques, which generally require diabetic subjects to prick their fingers for droplets of blood. Although numerous aspects must be improved, including more efficient interference rejection, better biocompatibility, and integrating sensors with readout and communication circuits, solutions to these problems should include the fabrication of a multifunctional contact lens to allow chemical analysis in the future.24

Valentín Huerva

Department of Ophthalmology

University Hospital Arnau de Vilanova

Avda Alcalde Rovira Roure 80

25198 Lleida

Spain

e-mail: vhuerva@gmail.com

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ACKNOWLEDGMENTS

The authors have no funding or conflicts of interest to declare.

Received January 20, 2015; accepted April 15, 2015.

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Keywords:

contact lenses; diabetes mellitus; biosensor; glucose control; tear glucose; noninvasive continuous glucose monitoring; fluorescence-based techniques; electrochemical determination; nanomaterials; noninvasive diagnostic device

© 2016 American Academy of Optometry