Tear Glucose Levels Research Articles

Electrochemical Sensors for Measurement of Glucose in Tiny Volumes of Tear Fluid

Tear glucose measurements have been suggested as a potential non-invasive alternative to blood glucose monitoring for diabetic patients [1,2]. While previous work has demonstrated a correlation between blood and tear glucose values in humans using complex LC-MS and capillary electrophoresis methods, this correlation has not been thoroughly established and additional clinical studies with a much larger patient population are sorely needed. This requires the availability of a very simple device that can quantitate the levels of glucose in tiny volumes (1 uL or less) of human tear fluid at the point of testing. Further, given the low levels of glucose found in tear fluid (10-300 µM), compared to blood plasma (3-15 mM), this creates a challenge for the conventional electrochemical measurement technologies typically employed for blood glucose measurements. In preliminary efforts toward achieving this goal, we utilized miniaturized needle type amperometric glucose enzyme electrodes that can be inserted into a microliter glass capillary tube to measure the levels of glucose in tear fluid obtained from anesthetized rabbits and proved that there was a reasonable correlation between blood and tear glucose levels [3,4]. However, the sensors employed in these first studies required 3 µL or more of tear fluid and the capillary tube was used to conveniently sample such volumes. A more attractive approach for determining glucose in < 1 µL tear volumes from human subjects is to use commercial electrochemical blood glucometer test strips in association with a laboratory quality, high current sensitivity potentiostat. Of many commercial blood glucose test strips evaluated, only one device has been found to be capable of achieving the low detection limits (< 10 µM) required for human tear glucose measurements. Using such strips, calibration data in the range of 0-300 μM glucose yield excellent precision and good selectivity over potential redox species found in tears (e.g., ascorbic and uric acids). Multiple measurements of glucose in tear fluid obtained from normal (non-diabetic) human subjects using commercial strips in conjunction with a laboratory potentiostat yield fasting tear glucose concentrations for non-diabetics within the range of 20-160 µM, similar to the values found by others using more complex LC-MS methods [1]. This glucometer strip based method could greatly facilitate more in depth clinical studies with a large number of patients (both normal and diabetic), to determine definitively whether tear glucose and blood glucose levels correlate well enough to enable routine measurements in tear fluid to supplement blood glucose testing.

Evaluation of Commercial Glucometer Test Strips for Potential Measurement of Glucose in Tears

Tear glucose measurements have been suggested as a potential alternative to blood glucose monitoring for diabetic patients. While previous work has reported that there is a correlation between blood and tear glucose levels in humans, this link has not been thoroughly established and additional clinical studies are needed. Herein, we evaluate the potential of using commercial blood glucose test strips to measure glucose in tears. Of several blood glucose strips evaluated, only one brand exhibits the low detection limit required for quantitating glucose in tears. Calibration of these strips in the range of 0-100 μM glucose with an applied potential of 150 mV to the working electrode yields a sensitivity of 0.127 nA/μM and a limit of quantitation (LOQ) of 9 μM. The strips also exhibit ≤13% error (n = 3) for 25, 50, and 75 μM glucose in the presence of 10 μM acetaminophen, 100 μM ascorbic acid, and 100 μM uric acid. Measurements of glucose in tears from nine normal (nondiabetic) fasting human subjects using strips yielded glucose values within the range of 5-148 μM (mean = 47 μM, median = 43 μM), similar to those for human tears reported by others with more complex LC-MS methods. The glucometer strip method could facilitate more clinical studies to determine whether tear glucose and blood glucose levels sufficiently correlate for application to routine measurements in tears to supplement blood glucose testing. This would be especially helpful for children, adolescents, other Type 1 diabetics, and also for Type 2 diabetics who require treatment with insulin and cannot tolerate multiple finger sticks per day.

A Disposable Tear Glucose Biosensor-Part 4: Preliminary Animal Model Study Assessing Efficacy, Safety, and Feasibility.

A prototype tear glucose (TG) sensor was tested in New Zealand white rabbits to assess eye irritation, blood glucose (BG) and TG lag time, and correlation with BG. A total of 4 animals were used. Eye irritation was monitored by Lissamine green dye and analyzed using image analysis software. Lag time was correlated with an oral glucose load while recording TG and BG readings. Correlation between TG and BG were plotted against one another to form a correlation diagram, using a Yellow Springs Instrument (YSI) and self-monitoring of blood glucose as the reference measurements. Finally, TG levels were calculated using analytically derived expressions. From repeated testing carried over the course of 12 months, little to no eye irritation was detected. TG fluctuations over time visually appeared to trace the same pattern as BG with an average lag times of 13 minutes. TG levels calculated from the device current measurements ranged from 4 to 20 mg/dL and correlated linearly with BG levels of 75-160 mg/dL (TG = 0.1723 BG = 7.9448 mg/dL; R2 = .7544). The first steps were taken toward preliminary development of a sensor for self-monitoring of tear glucose (SMTG). No conjunctival irritation in any of the animals was noted. Lag time between TG and BG was found to be noticeable, but a quantitative modeling to correlate lag time in this study is unnecessary. Measured currents from the sensors and the calculated TG showed promising correlation to BG levels. Previous analytical bench marking showed BG and TG levels consistent with other literature.

Wireless Tear Glucose Sensor

This paper presents a novel wireless tear glucose level sensor for diabetes patients. The miniaturized sensor can be worn non- invasively under the eye lid. It is composed of a chronoamperometric glucose sensor and an ASIC set with integrated potentiostat and transponder circuits. Wireless energy and data transmission according to the passive transponder standard ISO18000-3 is used to power and readout the sensor. A special coil shape enables high comfort for the patient. High integration level is achieved by a combination of antenna and sensor electrode wires. A complete demonstrator system including ASIC and sensor fabrication as well as assembly was manufactured and the function is demonstrated.

Biochemical studies of tears in patients with diabetes mellitus and dry eye syndrome

Aim. To study the lacrimal fluid glucose level in patients with diabetes and dry eye syndrome with hyperglycemia and after compensation. Methods. Glucose oxidase method was used to determine the level of glucose in tears of 40 patients with diabetes (80 eyes) who were treated at the endocrinology department. Of these, the diagnosis of diabetes mellitus (DM) type 1 has been established in 17 (42.5%) patients, type 2 - in 23 (57.5%). The study also included the control group, which included 20 healthy volunteers (40 eyes) aged 25 to 45 years (12 females, 8 males). Three groups were formed: healthy subjects, patients with diabetes mellitus and no signs of dry eye syndrome, patients with diabetes mellitus and clinical signs of dry eye syndrome. Results. Glucose level in the tear fluid of healthy individuals did not exceed 0.2 mmol/l. No signs of «dry eye» syndrome were found in patients with blood glucose levels up to 9 mmol/l (2nd clinical group). Patients of 3rd group were observed with the clinical symptoms with «dry eye» syndrome if there was an increase of blood glucose level over 17 mmol/l, tear glucose levels were also increased to 7 mmol/l. After the treatment the level of blood glucose in the patients of the second group decreased from 9 to 5 mmol/l, while tear glucose levels decreased from 1.2 to 0.5 mmol/l. In the third group the same clinical pattern was observed: reduction of blood glucose from 17.1 to 7 mmol/l was accompanied by a decrease of tear glucose levels from 7 to 1 mmol/l. There was a reduction of the subjective complaints characteristic for dry eye syndrome in patients from the third group. Conclusion. «Dry eye» syndrome is associated with increased tear glucose levels. The blood glucose level control is one of the methods of dry eye syndrome prevention in patients with diabetes mellitus.

Evaluation of enzyme-based tear glucose electrochemical sensors over a wide range of blood glucose concentrations

Miniature enzyme-based amperometric and coulometric glucose sensors were fabricated and applied to measure tear glucose concentrations in anesthetized rabbits. Without perturbing the eyeball, 3µL of tear fluid was sampled from the marginal conjunctiva under the lower eyelid of anesthetized rabbits at various time points via a microliter glass capillary tube, and the miniature sensors were then inserted into the volume of collected tear fluids within the capillaries for detection. Intravenous bolus doses of insulin were administrated to the rabbits to lower the elevated blood glucose concentrations caused by anesthesia over the 7h test periods. A significant correlation was found between tear and blood glucose levels for multiple rabbits, suggesting that electrochemical sensor-based tear glucose measurements may be a potential supplementary method for point-of-care glucose monitoring.

Miniature Enzymatic Biosensors for Tear Glucose Measurement in Capillary Tubes

Miniature enzymatic electrochemical sensors were fabricated and applied to detect tear glucose concentrations in anesthetized rabbits. Three µL of tear fluid was sampled from under the lower eyelid via a glass capillary, and the miniature sensor was then inserted into the solution within the capillary for detection. Boluses of insulin were administrated to the rabbits to lower the elevated blood glucose concentrations caused from anesthesia. A significant correlation was found between tear and blood glucose levels, suggesting that tear glucose measurements are a potential, minimally invasive alternative for glucose monitoring.

A contact lens with integrated telecommunication circuit and sensors for wireless and continuous tear glucose monitoring

We present an integrated functional contact lens, composed of a differential glucose sensor module, metal interconnects, sensor read-out circuit, antenna and telecommunication circuit, to monitor tear glucose levels wirelessly, continuously and non-invasively. The electrochemical differential sensor module is based on immobilization of activated and de-activated glucose oxidase. We characterized the sensor on a model polymer eye and determined that it showed good repeatability, molecular interference rejection and linearity in the range of 0–2 mM glucose, covering normal tear glucose concentrations (0.1–0.6 mM). We also report the temperature, ageing and protein-fouling sensitivity of the sensor. We report the design and implementation of a low-power (3 µW) sensor read-out and telecommunication circuit to deliver wireless power and transmit data for the sensor module. Using this small chip (0.36 mm2), we produced an integrated contact lens with sensors and demonstrated wireless operation of the system and glucose read-out over the distance of several centimeters.

Measurement of Tear Glucose Levels with Amperometric Glucose Biosensor/Capillary Tube Configuration

An amperometric needle-type electrochemical glucose sensor intended for tear glucose measurements is described and employed in conjunction with a 0.84 mm i.d. capillary tube to collect microliter volumes of tear fluid. The sensor is based on immobilizing glucose oxidase on a 0.25 mm o.d. platinum/iridium (Pt/Ir) wire and anodically detecting the liberated hydrogen peroxide from the enzymatic reaction. Inner layers of Nafion and an electropolymerized film of 1,3-diaminobenzene/resorcinol greatly enhance the selectivity for glucose over potential interferences in tear fluid, including ascorbic acid and uric acid. Further, the new sensor is optimized to achieve very low detection limits of 1.5 ± 0.4 μM of glucose (S/N = 3) that is required to monitor glucose levels in tear fluid with a glucose sensitivity of 0.032 ± 0.02 nA/μM (n = 6). Only 4-5 μL of tear fluid in the capillary tube is required when the needle sensor is inserted into the capillary. The glucose sensor was employed to measure tear glucose levels in anesthetized rabbits over an 8 h period while also measuring the blood glucose values. A strong correlation between tear and blood glucose levels was found, suggesting that measurement of tear glucose is a potential noninvasive substitute for blood glucose measurements, and the new sensor configuration could aid in conducting further research in this direction.

Biomedical soft contact-lens sensor for in situ ocular biomonitoring of tear contents

A soft contact-lens biosensor (SCL-biosensor) for novel non-invasive biomonitoring of tear fluids was fabricated and tested. Wearing a biosensor on eye enabled the in situ monitoring of tear contents. The biosensor has an enzyme immobilized electrode on the surface of a polydimethyl siloxane (PDMS) contact lens. The SCL-biosensor was fabricated using microfabrication techniques for functional polymers (PDMS and 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer). In investigation of in vitro characterization, the SCL-biosensor showed excellent relationship between the output current and glucose concentration from 0.03 to 5.0mmol·L(-1), with a correlation coefficient of 0.994. The calibration range covered the reported tear glucose concentrations (0.14mmol·L(-1)). Based on the result, ocular biomonitoring with the SCL-biosensor was carried out. The SCL-biosensor well worked both in the static state and the dynamic state. The tear glucose level of rabbit was estimated to 0.12mmol·L(-1) at first and then the tear turnover was successfully calculated to be 29.6 ± 8.42% min(-1). The result indicated that SCL-biosensor is useful for advanced biomonitoring on eye.

A contact lens with embedded sensor for monitoring tear glucose level

We report the design, construction, and testing of a contact lens with an integrated amperometric glucose sensor, proposing the possibility of in situ human health monitoring simply by wearing a contact lens. The glucose sensor was constructed by creating microstructures on a polymer substrate, which was subsequently shaped into a contact lens. Titania sol–gel film was applied to immobilize glucose oxidase, and Nafion ® was used to decrease several potential interferences (ascorbic acid, lactate, and urea) present in the tear film. The sensor exhibits a fast response (20 s), a high sensitivity (240 μA cm −2 mM −1) and a good reproducibility after testing a number of sensors. It shows good linearity for the typical range of glucose concentrations in the tear film (0.1–0.6 mM), and acceptable accuracy in the presence of interfering agents. The sensor can attain a minimum detection of less than 0.01 mM glucose.

Soft contact lens biosensor for in situ monitoring of tear glucose as non-invasive blood sugar assessment

A contact lens (CL) biosensor for in situ monitoring of tear glucose was fabricated and tested. Biocompatible 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer and polydimethyl siloxane (PDMS) were employed as the biosensor material. The biosensor consists of a flexible Pt working electrode and a Ag/AgCl reference/counter electrode, which were formed by micro-electro-mechanical systems (MEMS) technique. The electrode at the sensing region was modified with glucose oxidase (GOD). The CL biosensor showed a good relationship between the output current and glucose concentration in a range of 0.03–5.0 mM, with a correlation coefficient of 0.999. The calibration range covered the reported tear glucose concentrations in normal and diabetic patients. Also, the CL biosensor was applied to a rabbit for the purpose of tear glucose monitoring. The basal tear glucose was estimated to 0.11 mM. Also, the change of tear glucose induced by the change of blood sugar level was assessed by the oral glucose tolerance test. As a result, tear glucose level increased with a delay of 10 min from blood sugar level. The result showed that the CL biosensor is expected to provide further detailed information about the relationship between dynamics of blood glucose and tear glucose.

A soft and flexible biosensor using a phospholipid polymer for continuous glucose monitoring

A flexible biosensor using a phospholipid polymer to immobilization of glucose oxidase (GOD) was fabricated and tested. At first, an enzyme membrane formed by immobilizing GOD onto a porous polytetrafluoroethylene (PTFE) membrane using the phospholipid polymer (2-methacryloyloxyethyl phosphorylcholine (MPC) copolymerized with 2-ethylhexylmethacrylate (EHMA):PMEH) was evaluated. According to the result of amperometric measurement, average density of GOD to be immobilized was optimized to 38.9 units cm(-2). Temperature and pH dependences were also investigated. Then, a flexible glucose sensor was fabricated by immobilizing GOD onto a flexible hydrogen peroxide electrode using PMEH. The flexible glucose sensor showed a linear relationship between output currents and glucose concentration in 0.05-1.00 mmol L(-1), with a correlation coefficient of 0.999. The calibration range covered the normal tear glucose level of 0.14-0.23 mmol L(-1). This indicates that the flexible biosensor is considered to be useful for monitoring of glucose in tear fluids.

A flexible and wearable biosensor for tear glucose measurement

A flexible and wearable amperometoric glucose sensor was fabricated and tested. Also, the sensor was utilized to tear glucose monitoring. The sensor was constructed by immobilizing GOD onto a flexible oxygen electrode (Pt working electrode and Ag/AgCl counter/reference electrode), which was fabricated using "Soft-MEMS" techniques onto a functional polymer membrane. In purpose of bioinstrumentation, adhesive agents were not used for constructing the flexible biosensor. Linear relationship between glucose concentration and output current was obtained in a range of 0.025-1.475 mmol/l, with a correlation coefficient of 0.998. Current dependences on pH and temperature were also evaluated. The current was largest at pH 7.0 and the current increased when temperature increased. This indicates that the output current depends on enzyme activity. Based on the basic characteristics investigation, the glucose sensor was applied to measurement of glucose in tear fluids on an eye site of a Japan white rabbit. The change of tear glucose level induced by oral-administration of glucose was monitored as a current change of the sensor attached on the eye site. In this investigation, the tear glucose level varied from 0.16 to 0.46 mmol/l. Although there was a delay of several tens of minutes towards blood sugar level, it is considered to be possible that non-invasive continuous glucose monitoring can be realized using the flexible biosensor.

眼部における涙液グルコースモニタリング用ウエアラブルセンサ

A wearable glucose sensor for tear sugar measurement was fabricated and evaluated. The sensor was constructed by immobilizing glucose oxidase onto a flexible oxygen electrode, which was fabricated using "Soft-MEMS" techniques onto a functional polymer membrane. Linear relationship between glucose concentration and output current was obtained in a range of 0.049 to 1.37 mmol/l, with a correlation coefficient of 0.998. In addition to characteristics evaluation, the sensor was utilized to tear glucose measurement of a Japan white rabbit. The change of tear sugar induced by oral-administration of glucose was monitored as a current change of the wearable glucose sensor attached on the eye site. In this investigation, the tear glucose level varied from 0.3 to 0.93 mmol/l.

A glucose-sensing contact lens: from bench top to patient.

In the past few years we have seen the development of several new technologies for the continuous and non-invasive monitoring of physiological glucose, such as the GlucoWatch, glucose-sensing skin patches and approaches based on a glucose-sensing tattoo. One approach that differs from current thinking is based on the determination and monitoring of tear glucose, which is well known to track blood glucose with an approximate 30 min lag time, using disposable and colorless contact lenses. These contact lenses can be worn by diabetics who can colorimetrically see changes in their contact lens color or other fluorescence-based properties, giving an indication of tear and blood glucose levels.

Ophthalmic glucose monitoring using disposable contact lenses--a review.

We have developed a range of disposable and colorless tear glucose sensing contact lenses, using off-the-shelf lenses embedded with new water soluble, highly fluorescent and glucose sensitive boronic acid containing fluorophores. The new lenses are readily able to track tear glucose levels and therefore blood glucose levels, which are ideally suited for potential use by diabetics. The fluorescence responses from the lenses can be monitored using simple excitation and emission detection devices. The novelty of our approach is two fold. Firstly, the notion of sensing extremely low glucose concentrations in tears, which track blood levels, by our contact lens approach, and secondly, the unique compatibility of our new glucose signaling probes with the internal mildly acidic contact lens environment. The new lenses are therefore ideal for the non-invasive and continuous monitoring of tear glucose, with about 15-min response time, and a measured shelf life in excess of 3 months. In this review article, we show that fluorescence based signaling using plastic disposable lenses, which have already been industrially optimized with regard to vision correction and oxygen/analyte permeability etc, may a notable alternative to invasive and random finger pricking, the most widely used glucose monitoring technology by diabetics.

Ophthalmic glucose sensing: a novel monosaccharide sensing disposable and colorless contact lens.

We have developed a technology for continuous tear glucose monitoring, and therefore potentially blood glucose monitoring, using a daily use, disposable contact lens embedded with sugar-sensing boronic acid containing fluorophores. The novelty of our approach is two fold. Firstly, the notion of sensing extremely low glucose concentrations in tears by our approach, and secondly, the unique compatibility of our new probes with the internal environment of the disposable, off-the-shelf, contact lenses, chosen because the physiological compatibility of disposable plastic contact lenses has already been assessed and optimized with regard to vision correction, size and oxygen/analyte permeability. Our findings show that our approach is indeed suitable for the continuous monitoring of tear glucose levels in the concentration range (50-500 microM), which track blood glucose levels which are approximately 5-10 fold higher. We believe our approach offers unique opportunities for non-invasive continuous glucose monitoring for diabetics, especially since many have eye disorders and require vision correction by either contact lenses or glasses, which is thought to be due to glycation of protein in blood vessels.

A Glucose Sensing Contact Lens: A Non-Invasive Technique for Continuous Physiological Glucose Monitoring.

We have developed a range of glucose sensing contact lenses, using a daily, disposable contact lens embedded with newly developed boronic acid containing fluorophores. Our findings show that our approach may be suitable for the continuous monitoring of tear glucose levels in the range 50-1000 μM, which typically track blood glucose levels, which are ≈5-10 fold higher. Our non-invasive approach may well offer an alternative solution to current invasive glucose monitoring techniques for diabetes, such as "finger pricking."

Diabetic Keratopathy as a Manifestation of Peripheral Neuropathy

In a study of 102 patients (64 women and 38 men; 63 whites and 39 nonwhites; 77 with adult-onset disease and 25 with juvenile-onset disease), the data, after being adjusted for age, showed that diabetic peripheral neuropathy was associated with diabetic keratopathy. The strongest predictor of both keratopathy and corneal fluorescein staining was vibration perception threshold in the toes (P less than .01); the severity of keratopathy was directly related to the degree of diminution of peripheral sensation. Other predictors of keratopathy were reduced tear break-up time (P less than .03), the type of diabetes (P less than .01), and metabolic status, shown by fasting C-peptide levels (P less than .01). No significant relationships were found between keratopathy and tear glucose levels, endothelial cell densities, corneal thickness, or duration of disease.