Prototype of a Nanostructured Sensing Contact Lens for Noninvasive Intraocular Pressure Monitoring

Abstract

Purpose.: To present the application of a new sensor based on a flexible, highly piezoresistive, nanocomposite, all-organic bilayer (BL) adapted to a contact lens (CL) for non-invasive monitoring intraocular pressure (IOP).

Methods.: A prototype of a sensing CL, adapted to a pig eyeball, was tested on different enucleated pig eyes. A rigid, gas-permeable CL was designed as a doughnut shape with a 3-mm hole, where the BL film–based sensor was incorporated. The sensor was a polycarbonate film coated with a polycrystalline layer of the highly piezoresistive molecular conductor β-(ET)₂I₃, which can detect deformations caused by pressure changes of 1 mm Hg. The pig eyeballs were subjected to controlled-pressure variations (low-pressure transducer) to register the electrical resistance response of the CL sensor to pressure changes. Similarly, a CL sensor was designed according to the anatomic characteristics of the eye of a volunteer on the research team.

Results.: A good correlation (r ² = 0.99) was demonstrated between the sensing CL electrical response, and IOP (mm Hg) changes in pig eyes, with a sensitivity of 0.4 Ω/mm Hg. A human eye test also showed the high potential of this new sensor (IOP variations caused by eye massage, blinking, and eye movements were registered).

Conclusions.: A new nanostructured sensing CL for continuous monitoring of IOP was validated in an in vitro model (porcine eyeball) and in a human eye. This prototype has adequate sensitivity to continuously monitor IOP. This device will be useful for glaucoma diagnosis and treatment.

Glaucoma is the second leading cause of irreversible blindness worldwide. ¹ Its prevalence varies between 1% and 3%, depending on the population studied and the diagnostic criteria. ^2,3 Moreover, glaucomatous optic neuropathy leads to certain characteristic changes in the optic nerve head and visual field loss and is usually associated with increased intraocular pressure (IOP), with values higher than 21 mm Hg. ²  

However, one of the most important parameters in glaucoma diagnosis and treatment is IOP measurement because the primary treatment goal is to reduce IOP to prevent optic nerve damage. IOP fluctuates during the day, with a maximum value at daybreak and a minimum at the end of the afternoon. ⁴ This fluctuation is partially related to circadian rhythms, ⁴ but IOP can also be influenced by other factors, such as accommodation, ⁵ action of the extraocular muscles (convergence), ⁶ blood pressure, ⁷ atmospheric pressure, ⁸ blinking, ⁶ and others (e.g., body position, Valsalva maneuvers). ^{6,9 –11} The only reliable method to determine whether IOP increases at any time of the day is to construct a 24-hour tensional curve with the patient in a hospital environment. ⁴ Thus, the measurement and monitoring of IOP is a widely studied aspect in the literature. Hughes ¹² showed that monitoring IOP for 24 hours may change the clinical management of a high percentage, >70%, of patients with glaucoma. 

Attempts to continuously monitor IOP have been made, but none of the devices developed has been integrated into clinical practice mainly because of technical problems, lack of long-term stability, and other issues. ^{13 –17} Some devices to monitor IOP are based on the principle that a change in IOP of 1 mm Hg causes a change in corneal curvature of 3 μm for a corneal radius of 7.80 mm. ^10,18  

The purpose of this study was to present a proof of concept of the application of a new sensor based on a conducting, all-organic, nanocomposite bilayer (BL) adapted in a contact lens (CL) for noninvasive monitoring of IOP. 

Materials and Methods

Contact Lens Sensor

A rigid, gas-permeable CL material (Boston XO2; Conoptica SL, Barcelona, Spain) was designed according to the anatomic characteristics of the pig eye to ensure an adequate flat fitting that enabled us to measure and register any changes in the apex corneal curvature induced by IOP alterations. The CL was designed according to the pig eye corneal radius and corneal topography (Orbscan II, version 3.12; Bausch & Lomb, Rochester, NY). ¹⁹ The CL was doughnut-shaped (central hole diameter 3.0 mm). A round membrane based on a piezoresistive BL film was glued over the hole. Two delicate Pt-based wires, each with a diameter of 20 μm, were attached to the sensing layer of the BL film-based membrane with graphite paste and were connected with two copper wires, each with a diameter of 50 μm. The prototype is shown in Figure 1. The electrical connection was configured in such a way as to minimize sensor deformation. The developed electrical connection enabled the sensing lens to access the recording apparatus, a discrete device specifically designed for this study. This device was connected with a wireless device (Bluetooth, Kirkland, WA) to a personal computer to continuously register the measurements of the CL sensor. 

Figure 1.

 

Schematic view (top) and image (bottom) of the IOP sensing lens composed of a doughnut-like contact lens (1), the highly piezoresistive BL film-based membrane (2), and electrical connections with a linear configuration of the contacts. Two 20-μm-thick Pt wires (3) are attached to the conducting layer of the membrane using graphite paste (4). The Pt wires are attached to 50-μm-thick Cu wires (5), which are connected to the collecting data device.

A flexible, highly piezoresistive BL film, with the molecular metal β-(ET)₂I₃ (bis-[ethylenedithio]tetrathiafulvalene) as a sensing component, was prepared using a previously reported synthetic method. ^{20 –22} The texture, structure, and electromechanical properties of the prepared BL film, which were characterized by different spectroscopic and microscopic techniques and by resistance-pressure measurements, were identical with those reported; in the laboratory, the BL film was able to detect deformations caused by a pressure change of 1 mm Hg, which fulfills the requirements of glaucoma control device. ^23,24 Nearly circular membranes were cut from the prepared BL film sample and were used as a sensing element to register changes in IOP. To avoid damaging the sensing BL film-based membrane, it was covered by an additional “cap” piece made of the same material as the rigid contact lens. 

In Vitro Experimental Procedure

Thirty enucleated pig eyes were used. The eyeballs were collected in the local slaughterhouse immediately after the animals were euthanatized, for which the age ranged between 6 and 8 months. After enucleation, pig eyes were kept in ice and immersed in Dulbecco's modified Eagle's medium supplemented with antibiotic/antimycotic mixture (Gibco, Paisley, UK). Measurements were conducted within 4 hours to preserve the elastic properties of the ocular tissues. 

The pig eyeballs were subjected to controlled-pressure variations to register and compare them with the variations in resistance taken by the sensor CL (Fig. 2). A 23-gauge cannula was inserted in the vitreous chamber, 3.5 mm from the sclerocorneal limbus, and Ringer's lactate solution was injected through a closed system using a glass bottle as a water column controlled by a low-pressure transducer (CPC 2000; WIKA Alexander Wiegand GmbH & Co., Klingenberg, Germany). The transducer permitted the increase, decrease, and maintenance of IOP in a range of 20 to 55 mm Hg. ²⁵  

Figure 2.

 

Schematic representation of in vitro experimental design.

The sensing CL demonstrated good hydrostability; therefore, it was placed on the ocular surface on the porcine eye and hydrated with distilled water without any precaution. The sensing lens was connected to the discrete device made for this project, which registered the changes in electrical resistance captured by the sensor CL as a result of changes induced in IOP. 

Output signals of the low-pressure transducer (mm Hg) and the sensing CL electrical resistance changes (Ω) were automatically stored on the same computer, registering every 5 seconds. The graph of the IOP changes was compared to the electrical changes recorded by the sensing CL. To minimize the temperature effect, all pressure tests on cannulated pig eyes were carried out at a stabilized temperature, using another sensing lens that revealed the same temperature resistance coefficient as the temperature reference. The correlation between the change in IOP induced by low-pressure transducer and the CL sensor measurements was calculated with the r ² coefficient. 

In Vivo Experimental Procedure

A CL sensor was designed and flat fitted to the eye of a volunteer on the research team. This CL was made according to the subject's corneal topography (Orbscan II, version 3.12; Bausch & Lomb). Flat fitting was used to guarantee that the sensor film would detect corneal curvature changes related to IOP changes. The CL was worn for 2 hours to register the influence of blinking and eye movements on the sensor's electrical response. 

The ocular surface of the volunteer was anesthetized with oxybuprocaine hydrochloride and tetracaine hydrochloride, and a therapeutic CL (Purevision; Bausch & Lomb) was fitted to protect the cornea. The CL sensor was piggyback fitted onto this. 

A discrete device for conditioning and digitizing the data has been designed. The device was powered by a battery and had an internal memory to operate while it autonomously saved data for 24 hours. The CL sensor was wire connected to the discrete device accessory to continuously register the measurements of the CL sensor caused by blinking, eye movements, and IOP fluctuations. This device was wirelessly (Bluetooth)–connected to a personal computer to allow the patient to move without restriction while measurements were performed. 

The Human Sciences Ethical Committee of the University of Valladolid, Spain, approved this protocol. The subject was treated in accordance with the Declaration of Helsinki. 

Results

In Vitro Experimental Results

The pig eyeballs were stimulated by applying controlled changes of increasing and decreasing IOP so that the sensing CL registered periods of electrical resistance values with an excellent time agreement. Figure 3 shows the recorded IOP changes induced by the low-pressure transducer and the output signal (ΔR) of the sensing CL. We collected data for all five up-down (Fig. 3) pressure steps and plotted the resistance changes (ΔR) to determine the sensitivity of the CL sensor (Fig. 4). The graph shows a linear correlation between IOP and sensor resistance response (r ² = 0.99), with a sensitivity of 0.4 Ω/mm Hg. 

Figure 3.

 

Representation of IOP variations and CL sensor outputs over time in a single study eye. Gray solid line: pressure changes (mm Hg); black dotted line: electrical resistance (Ω) variations. Pressure changes (up and down) and resistance changes showed similar trends. When pressure was constant (20 mm Hg or 50 mm Hg), resistance was also constant.

Figure 4.

 

Calibration of the CL sensor. Changes in the electrical response of the lens to IOP variations on a pig eye induced using a low-pressure transducer are plotted. Data were collected from the five up-down steps shown in Figure 3. A high linear correlation between IOP and sensor resistance changes was found (r ² = 0.99), with a sensitivity of 0.4 Ω/mm Hg.

In Vivo Experimental Results

No relevant clinical biomicroscopic signs (grade >2; Efron grading scales) of CL complications (corneal staining, limbal injection, or other) were found. Figure 5 shows the 2-hour plot of the output signal of the CL sensor while it was fitted to the volunteer's eye. Variations in electric resistance were caused by massage of the eye, strong blinking, and eye movements. These results show the high potential of this new sensor to monitor IOP for extended periods of time. 

Figure 5.

 

Results of an in vivo experiment. Gray line: changes in the resistance of the CL caused by increases in IOP produced by gentle pressing of the eye and strong blinking.

Discussion

Accurate IOP monitoring is important for glaucoma patients because increased IOP causes retinal ganglion cells to die, leading to irreversible blindness. ^{26 –28} For this reason, much research has focused on developing methods and devices to monitor IOP. The first attempt was made by Maurice, ¹³ but Greene and Gilman ¹⁴ published the first noninvasive IOP-monitoring system using a CL device in rabbits. In addition, Wolbarsht ¹⁵ designed a pressure transducer on a band that recorded IOP, Flower ¹⁶ tested an IOP-measuring system in adult rhesus macaque (Macaca mulatta) monkeys, and Svedbergh ¹⁷ created an intraocular lens to measure IOP. Leonardi ^11,18 has developed a marketable prototype of a hydrophilic sensor CL to indirectly measure IOP. This prototype measures deformations of the eyeball (changes in corneal curvature) caused by IOP variations and uses a soft CL with a platinum-titanium strain gauge, or it uses an invasive method such as the sensor for monitoring IOP. ^29,30 Recently, Mansouri and Shaarawy ³¹ reported the clinical use of a wireless ocular telemetry sensor described by Leonardi ¹⁸ with device intolerance and technical device malfunction in 13% of the patients tested. In addition, Twa et al. ³² have proposed a novel contact lens–embedded pressure sensor, but this sensor cannot permit prolonged use beyond 30 minutes or the wireless connection necessary for IOP monitoring. 

CL Sensor

Some of the devices proposed to monitor IOP are based on the principle that a change in IOP of 1 mm Hg causes a change in the corneal curvature of 3 μm, given a corneal radius of 7.80 mm. ^10,18,31 By engineering composite materials at the submicrometer or nanometer scale, it is possible to obtain flexible and highly conductive BL films that contain organic molecular conductors such as a coating metallic or semiconductor-like layer. ^{20 –22,33} These BL films combine properties that are difficult to reconcile (e.g., flexibility, transparency, electrical conductivity, long-term stability, and light weight). One such BL film is a polycarbonate film coated with a metallic polycrystalline layer based on the organic molecular metal β-(ET)₂I₃. This electroconductive BL film can sense resistance to strain with extremely high sensitivity; the film is able to sense a relative strain of ≈10⁻³%. ^23,24 The electrical resistance responses of the BL films to strain are 3 to 10 times greater than those exhibited by inorganic metal-based gauges. The BL film can be used as a pressure-sensing membrane in pressure sensors with a sensitivity of 1.4 Ω/mm Hg, ^23,24 which is higher than the sensitivity of other IOP contact lens sensors. ^18,31  

Another advantage of this piezoresistive material is its transparency: BL films show transparency up to 70% to 80% ³³ of the visible spectrum (550–900 nm). Therefore, the BL film–based sensor must function reliably when size, performance, robustness, light weight, and transparency are important. The BL film embedded as a membrane in a CL can be applied as a highly sensitive pressure sensor that fulfills the requirements of a noninvasive IOP-monitoring device. We found that the developed CL sensor has good sensitivity (0.4 Ω/mm Hg) that be used in noninvasive IOP monitoring as well-defined electrical signals. The electrical resistance response of one of the prototypes of sensing lenses, reported by Leonardi et al., ³⁷ was only 0.4 Ω for maximum pressure fluctuation. 

Electronic Measurements

In developing an IOP-monitoring system, electronic measurements are responsible for conditioning the signal from the pressure sensor embedded in the lens, digitizing it, and transmitting it to an external device. In the final prototype, the electronic measuring system should be embedded in the CL to avoid possible patient discomfort caused by any wires to and from the sensor lens. The measured data must then be wirelessly transmitted to a data acquisition system. However, because of the reduced area available on the lens, the system cannot be battery powered, which would also require a wireless energy transmission system. Wireless power transmission implies the design of very small and low-power electronic measuring devices, which can only be achieved through the development of an application-specific integrated circuit (ASIC). ³⁴  

In future, the integrated electronic measurement system will be improved and further developed to avoid the use of wires. The purpose of this device was to establish the membrane characteristics and study the feasibility of the circuitry to successfully develop the ASIC. Therefore, all tests with the discrete device had to be performed to establish the system specifications. At the same time, it could be used to study the effects of blinking, tears, and temperature to determine whether they could be filtered by either software or hardware. 

To satisfy all requirements, the system's structure was based on a special configuration of a Wheatstone bridge. ³⁵ It was formed by four branches, and the sensor was placed in one of them. This configuration permitted only the measurement of IOP variations, eliminating the absolute value and reducing the measurement scale and thereby simplifying data acquisition and permitting increased resolution of the measurements. 

This structure was integrated and sent data wirelessly. To enable data modulation, the measurement circuit converted the data into pulses using a pulse density modulation system. ³⁴  

Current discrete devices that are wired to the sensing CL can be used to take measurements for a few hours, but they may not be comfortable enough to be used for a long time. For this reason, our system should work wirelessly, allowing patients to perform normal activities while recording the fluctuations of their IOP throughout the day. Therefore, an integrated device, or ASIC, embedded in the CL and powered by an inductive link will be developed. The antenna of the inductive link will be also embedded in the lens to receive energy from an external device and to transmit the measured data from the sensor. 

Clinical Implications

Continuous monitoring of IOP could be of paramount importance in patients with suspected glaucoma, such as the patient with normal IOP values but a pattern of visual field loss and optic nerve head changes suggestive of normal tension glaucoma. Continuous monitoring could also be used in glaucoma patients to check the IOP values and modify patient management. ¹² Thus far, the only clinically proven method known to determine whether IOP increases at any time of the day is to conduct a 24-hour tensional curve with the patient in a hospital environment. ⁴  

A CL sensor able to record the IOP changes could be a useful, noninvasive, easy-to-handle, and inexpensive tool that would find clinical application in glaucoma diagnosis. This study presents proof of concept of a new method for continuous monitoring of IOP, based on a sensing CL, in an in vitro model of porcine eyeball and in a human eye to validate this measurement principle. In humans, eye movements and blinking are filtered from the signal so that they do not interfere with the monitoring of IOP. They are easily distinguishable because they are observed as a disturbance in the sharp and short signal. It should be noted that fluctuations in corneal thickness and hydration could induce an anterior flattening of the corneal curvature that could affect IOP measurements. ³⁶ The effect of diurnal variation of the cornea must be assessed in further investigations. 

This new CL sensor is not free of limitations, similar to previous CL sensors described in the literature. ^18,31,32,37 Sensor transparency must be improved to avoid visual disturbances to the patient. Individual patient-tailored calibration could be necessary because corneal curvature change caused by IOP change depends on the basal corneal radius. The IOP value depends on corneal thickness. In addition, like current CL sensors, our sensor measures IOP change, ^18,31,37 but this is not the IOP magnitude itself. Finally, a filtration procedure must be designed to differentiate the signal caused by IOP fluctuation of the noise related to such activities as blinking and eye movement. These issues must be resolved before commercial and clinical use of this new prototype, but the results of this study show that this prototype has adequate sensitivity to continuously monitor IOP, which could be very useful for diagnosing and treating glaucoma. In future, this may allow a CL sensor to be developed that would be minimally invasive and would continuously monitor IOP for 24-hour periods, allowing the patient to maintain a normal lifestyle while using the CL sensor, with minimal interference with vision and with highly accurate measurement of IOP variations. 

Footnotes

 Supported by CIBER-BBN, an initiative funded by the VI National R+D+i Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions; by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund, Generalitat de Catalunya, under the framework of Programa Operatiu FEDER de Catalunya, contract VALTEC09-1-0030; and by project SGR2009-516, the European Union Large Project One-P (FP7-NMP-2007-212311), the DGI, Spain, projects CTQ2006-06333/BQU and CTQ2010-19501/BQU.

Footnotes

 Disclosure: I. Sánchez, None; V. Laukhin, P; A. Moya, None; R. Martin, None; F. Ussa, None; E. Laukhina, P; A. Guimera, None; R. Villa, None; C. Rovira, P; J. Aguiló, None; J. Veciana, P; J.C. Pastor, None

The authors thank Conoptica Company for supplying and manufacturing the doughnut-shaped contact lenses.