Full contact

Bausch & Lomb commercialised the first soft contact lenses, made from a hydrogel, in 1971. The next generation of lenses incorporated silicone-containing polymers to increase comfort. Now, some researchers have turned their attention to ‘smart’ contact lenses, exploiting miniaturised electronics and transparent conducting materials. In future, it may be that our lenses won’t just improve vision, but will also monitor biomarkers of disease by measuring levels of sugars and proteins in our tears.

Smart lenses for continuously monitoring glucose are a major research area. In recent years, continuous glucose monitors (CGM) have entered the market, providing patients with more data and allowing tighter control over glucose levels. But CGM have drawbacks: most require inserting electrodes under the skin, which can be painful and can cause skin problems.

Gregory Herman’s team at Oregon State University (OSU), US, are using flexible, transparent sensors to monitor glucose levels in the tears of Type 1 diabetes patients. Ultimately, the researchers want to expand the sensors to detect a range of tear biomarkers to identify ocular disorders such as dry eye disease, diabetic retinopathy and glaucoma, cancers and multiple sclerosis.

The group’s technology was developed initially for consumer electronics. While working in industry, Herman and two colleagues developed a semiconductor based on indium gallium zinc oxide (IGZO) that produced higher resolution displays on televisions, smartphones and tablets while saving power and improving touch-screen sensitivity. In 2009, Herman moved to OSU, where he began investigating biomedical applications.

‘These biosensors probably won’t put blood labs out of business,’ says Herman. ‘But I think that we can do a lot of diagnostics using information that can be extracted from tear drops in the eye.’

Herman’s team created a biosensor containing a transparent sheet of IGZO field-effect transistors (FETs) and glucose oxidase, an enzyme that breaks down glucose.1,2 The enzyme oxidises any glucose present, resulting in a pH change, which triggers a response in the electrical current flowing through the IGZO transistor. ‘We use field effect sensing which measures changes in the electric field near a surface, which in turn changes the conductivity of the semiconductor material,’ Herman says.

However, glucose concentrations in the eye are much lower than in blood or interstitial fluid under skin so lens biosensors have to be much more sensitive. To address this problem, the team uses colloidal nanosphere lithography to minimise the size of the semiconductor molecule (amorphous indium gallium) in the active layer. The resulting closely packed, hexagonal nano-networks can detect subtle glucose changes in tear fluid. ‘This scaleable technique improves sensing by about two to three times order of magnitude - so well within the range of detecting glucose in tears,’ says Herman.

Their goal is to integrate the sensor in a contact lens where it operates as part of an artificial pancreas. The sensor could transmit real-time glucose information to a wearable pump that delivers the hormones needed to regulate blood sugar: insulin and glucagon.

The team is investigating using a capacitor to store charge and power the sensors. ‘The capacitor could be charged using radiofrequency communications,’ explains Herman. ‘As the sensors would be very small and would not run all the time, ideally they would not use a lot of power.’

In theory, Herman says more than 2500 biosensors - each measuring a different bodily function - could be embedded in one millimetre square patch of an IGZO contact lens. ‘We can integrate an array of sensors into the lens and also test for other things: stress hormones, uric acid, pressure sensing for glaucoma, and characteristic protein biomarkers of cancer risk. We can monitor many compounds in tears – and since the sensor is transparent, it doesn’t obstruct vision; more ‘real estate’ [area] is available for sensing on the contact lens.’

Once they are fully developed, the biosensors could transmit vital health information to smartphones and other Wi-Fi or Bluetooth-enabled devices. However, Herman says it could be a year or more before a prototype bio-sensing contact lens is ready for animal testing.

Dual purpose lenses

Researchers in South Korea are also working on contact lenses to monitor glucose in tears, but their devices are also designed to measure high intraocular pressure. Intraocular pressure is the largest risk factor for glaucoma, a leading cause of blindness. The team – led by Jang-Ung Park at Ulsan National Institute of Science and Technology and Hong Kyun Kim at Kyungpook National University - has demonstrated real-time glucose detection on a live rabbit eye and in vitro wireless monitoring of intraocular pressure of a bovine eyeball. Their sensor measures both glucose and intraocular pressure simultaneously based on different electrical responses.

‘This study can be used to diagnose diabetes and glaucoma by implementing two types of transparent electronic sensors in the production of smart contact lens sensors,’ says Park. ‘We are now a step closer to the implementation of a fictional idea for a smart contact lens like in the films Minority Report and Mission: Impossible.’

The sensor’s key components are graphene and a graphene-silver nanowire (AgNW) hybrid structure, which has enhanced electrical and mechanical properties while still maintaining transparency and ‘stretchability’. The team integrated the sensors with resistance, inductance and capacitance circuits and placed them onto soft contact lenses. All the components are transparent, with slightly visible spiral antenna. The circuits operate at a radio frequency so power sources are not required, the team adds.

To monitor intraocular pressure, the team placed a layer of silicone elastomer between two inductive spirals made of graphene-AgNW hybrid electrodes in a sandwich structure.3 High-intraocular pressure increases the radius of curvature of the cornea. As pressure rises, the cornea stretches and the dielectric layer in the sensor - an electrically non-conductive layer - starts to thin, and this increases the capacitance of the circuit. At the same time, the spiral coils also start to expand and this increases the inductance. The sensor embedded in the contact lens transmits the changes in both to the wireless antenna.

Whereas inductance and capacitance vary with structural changes in the device, allowing the detection of intraocular pressure, the circuit’s resistance responds to molecular binding. To detect glucose, the team use glucose oxidase immobilised on channels in the graphene using a pyrene linker. The enzyme catalyses oxidation of glucose to gluconic acid and reduction of water to hydrogen peroxide. Hydrogen peroxide, a reducing agent in the system, is oxidised to produce oxygen, protons and electrons. The concentration of charge carriers in the channel, and thus the drain current, increases at higher concentration of glucose, and this affects the resistance in the circuit, which can be detected and measured.

Although the team admits that the precise diagnosis of glucose may require further sensor development, they say that the contact lens sensor should be sufficient for screening for prediabetes and daily glucose monitoring. They also expect that the simple pyrene-chemistry involved would allow for a multiplexed array of graphene sensors, tuned to detect numerous disease-related biomarkers in tear fluid.
According to the team, the sensors still worked when the lens changed shape, and when exposed to various substances in human tears. Furthermore, since the electronic sensor is inserted into a soft contact lens, they claim it should feel comfortable and note that the rabbit did not show any abnormal behaviour when wearing the lens.

Autofocus lens

Another area of research of interest are lenses that focus themselves within milliseconds. These could be life-changing for people with presbyopia or age-related far-sightedness, in which the eye’s lens gets stiffer so making it difficult to focus on close objects.

Presbyopia affects more than 1bn people worldwide, half of whom do not have adequate correction, says Hongrui Jiang of the University of Wisconsin, Madison, US. And while glasses, conventional contact lenses and surgery provide some improvement, these options all involve the loss of contrast and sensitivity, as well as difficulty with night vision. Jiang wants to design contacts that continuously adjust along with a person’s own cornea and lens to restore better vision.

The project requires overcoming several engineering challenges. These include designing the lens, algorithm-driven sensors and miniature electronic circuits that adjust the shape of the lens, plus creating a power source. All of these then need to be embedded in a soft, flexible material that fits over the eye.

In their latest study, Jiang’s team has been investigating image sensors.4 ‘The sensors must be extremely small and capable of acquiring images under low-light conditions, so they need to be exquisitely sensitive to light,’ he says.
The team took their inspiration from the retina of elephant nose fish, which live in dark, muddy rivers. The fish can spot predators even in murky waters because of their uniquely shaped retina, which comprises a series of parabolic or cup-like structures with reflective sidewalls that help gather light and intensify the particular wavelengths needed for the fish to see.

The researchers created a device with thousands of very small light collectors; shaped like fingers, the insides of these glass collectors are lined with deep cups coated with reflective aluminum. Incoming light hits the fingers and then is focused by the reflective sidewalls. Jiang’s team tested the device’s ability to enhance images using a lab-designed mechanical eye model. They found it enhanced image intensity without consuming power.

In separate studies, the researchers have designed and lab-tested a couple of different approaches for the contact lens material. For one approach, they formed a liquid lens from a droplet of silicone oil and water. The droplet sits in a chamber on top of a flexible platform. A pair of electrodes produces an electric field that modifies the surface tension of each liquid differently, resulting in forces that squeeze the droplet into different focal lengths. The team reported that their lens is able to focus on objects as small as 20µm, roughly the width of the thinnest human hair.

In another approach, the team have tried to mimic the compound eyes of insects, which contain thousands of individual microlenses. Each micolens points in different directions to capture a specific part of a scene. Jiang’s team developed a flexible array of artificial microlenses. ‘Each microlens is made out of a forest of silicon nanowires,’ Jiang explains. ‘Together, the microlenses provide even greater resolution than the liquid lens.’

In order to change focus, the contact lens will also need to be equipped with an extremely small, thin power source. Jiang’s working solution is a solar cell that converts solar energy into electricity, and also stores energy within a network of nanostructures. It works much the way a conventional solar panel does, but the addition of storage capability within a single device is novel, according to Jiang. The device still needs tweaking, but the team is optimistic that it will be powerful enough to drive the lens yet small enough to fit the space available.

A prototype for clinical testing may still be five to ten years off, Jiang says. Once it’s available, however, it may not cost much more than conventional contact lenses. ‘There's a huge market for this and with mass production, the cost is not likely to be a barrier,’ he believes.

References
1   G. Herman et al, Nanoscale, 2016, 8, 18469.
2   G. Herman et al, ACS Appl. Mater. Interfaces, 2016, 8, 7631.
3  Jang-Ung Park et al, Nature Communications; DOI: 10.1038/ncomms14997.
4  H. Jiang et al, PNAS; DOI: 10.1073/pnas.1517953113.