Technological advances have the potential to increase our worldwide contact lens wearer base—estimated currently to be roughly 125 million to 140 million lens wearers, and make headway into non-traditional markets and populations.¹ This broadening of the wearer base presents great opportunities, but also raises new clinical questions that will help identify future research agendas. In this article, we will discuss three areas of contact lens research: myopia control, safety and drug delivery.

Myopia Control
High myopia is a significant public health issue, particularly in Asian populations, and is associated with greater risk of retinal detachment, choroidal degeneration, glaucoma and early cataract.² There is some evidence that contact lens-related adverse events occur more often in high myopes, most likely due to increased reliance on contact lenses.^3,4

Corneal reshaping techniques (CRT) were introduced in the early 1960s.⁵ In the 1990s, new designs—e.g., reverse geometry and the use of high Dk materials—ensured sustained reproducible effects after overnight wear. Recent clinical trials have confirmed anecdotal reports of myopia retardation due to decreased axial length with CRT.^5,6

There was early hope that alignment fitting rigid lenses would decrease myopia; however, randomized controlled trials indicated that there was only flattening of the cornea and no significant changes in axial length.⁷ Adaption is less of an issue with overnight vs. daily wear of rigid gas-permeables. However, in addition to easy adaption, soft lens designs require less skill and specialized equipment to fit—thus broadening the market to reach a greater number of wearers.

A 2004 study found an association between low Dk soft lenses (but not high Dk silicone hydrogels) and an increase in myopia over time.⁸ Soft bifocal lenses have shown good efficacy in myopes with high accommodative lag and esotropia.⁹ Twin studies also indicate a beneficial effect in these groups.¹⁰

Recently, dual focus lenses that induced myopic defocus simultaneously with distance vision have shown promising results.¹¹ These lenses are marketed in Asia as MiSight daily disposable lenses (omafilcon A, CooperVision). Although the mechanism is unknown, it is thought to be related to reduced peripheral defocus rather than driven by reducing accommodative stimuli.

Hyperopic peripheral defocus as a stimulant to myopic progression has been established through animal studies.¹² Novel contact lenses correcting for peripheral hyperopic defocus are in clinical trials and have been shown to decrease myopic progression compared to spectacles.¹² While the decreases are modest, the results are promising. Increased research into eye shape and development is likely to fuel lens design innovations and improve outcomes.

There has been concern regarding the safety of overnight wear of corneal reshaping lenses following reports of microbial keratitis in East Asia in the early 2000s. It is understood that these cases occurred with overnight wear of low Dk lenses, which may not have been fitted or cared for appropriately.¹³ Recent clinical trials and anecdotal reports indicate low levels of adverse events, albeit at early age.¹⁴ With the current results, residual ametropia is likely to be an issue for the majority of children targeted. Long-term effects of reshaping the eye and extended years of lens wear in terms of ocular surface biocompatibility, encompassing the lids and conjunctiva as well as the cornea, should be monitored.

Recent investigations into one-year wear of corneal reshaping lenses in young adults (ages 18 to 30) showed corneal changes that were not reversible one month after ceasing wear, including increased endothelial polymegethism, thinning of Bowman’s layer and sub-basal nerve plexus.¹⁵

As we learn more about the factors that contribute to myopia (i.e., light levels, nutrition, near work and genetics), it is probable that enhanced myopia onset and retardation results using contact lenses could significantly lower the proportion of severe myopes. We do still have lingering questions as to what age and level of refractive error is optimal to introduce contact lens wear. Well-designed, long-term controlled epidemiological studies, as well as continued animal and in vitro investigations, will be required to improve success and ensure that the long-term health of the anterior eye is not compromised to the extent that it is predisposed to adverse events or restricted in lens wearing options down the road.

Compliance and Safety
Microbial keratitis (MK) presents with less severity (0.5x) but the same incidence in daily disposables vs. other soft lenses.^16,17 The lower severity of MK in daily disposables suggests that the frequency of replacement may affect organisms differently. Specifically, eliminating the storage case may remove the source of environmental pathogens. This is important because environmental organisms are associated with a greater frequency of vision loss and more severe disease phenotype.¹⁸ Keep in mind that the rate of MK varies with different daily disposable lens types, with etafilcon A having the lowest in a recent study.¹⁷ This may be related to difficulties with lens removal with other lens types.¹⁷

Researchers concluded that the incidence of corneal erosions with lenses contaminated with gram-negative bacteria was comparable to the rate of microbial keratitis rates for different lens modalities.¹⁸ In a clinical trial of 278 daily disposable wearers (etafilcon A, 1 Day Acuvue, Vistakon) over a 12-month period in India, no cases of corneal erosions occurred.¹⁸ Mark Willcox, Ph.D., and colleagues found that gram-negative contamination of these daily disposable lenses also was the lowest compared to frequent replacement daily and extended wear lenses.¹⁸
Case reports of severe Pseudomonas aeruginosa, Acanthamoeba and fungal keratitis with daily disposables do exist in the literature.^19-22 As the market penetration increases and new lens types are introduced, we must continue to monitor infection and severe inflammation rates, and continue surveillance for emerging organisms.

A large-scale study of compliance in Canada and the United States found that daily disposable wearers were more compliant with the practitioner’s recommended replacement schedule than their two-week and monthly counterparts.²³ The majority of non-compliant daily disposable wearers stated cost was the primary reason.²³ In the U.S., one-fifth of non-compliant wearers said they did not see any harm in not replacing lenses daily.²³

These users may be tempted to wear the lenses overnight—doing so increases the chance of infection four-fold. Another common error is to place the lens back in the blister pack that contains no active disinfectant, which increases the chance of infection.¹⁶ A record card review study in the U.S. found that a higher proportion of daily disposable wearers reported non-compliant overnight wear compared to other lens wear modalities.²⁴
A recent study highlighted the dangers of reusing daily disposable lenses.²⁵ Twenty daily disposable wearers participants transferred their lenses back into the blister pack, and then into a new case with the blister pack solution, after a full day of wear on five occasions. In 95% of wearers, at least one lens was contaminated—the predominant organism was the gram-positive staphylococci. Six out of the 20 wearers admitted to previous reuse of lenses from the blister packs. What we can learn is that continual daily disposable education is just as vital in this modality, particularly as users may believe they have less chance of complications and, therefore, take more risks.

Several contact lens manufacturers have recently introduced novel technologies, such as incorporating wetting agents within lenses and solution blister packs, and developing new lens materials and manufacturing techniques. These enhancements are designed to encourage new lens wearers to the market, reduce the dropout rate and improve the comfort of current wearers.

When disposable lenses were first introduced into the market, the rate of microbial keratitis was artificially high.²⁶ As more of the population were fitted with disposable lenses the rate fell. It is believed that the artificial increase in the infection rate can be attributed to a high number of lenses being fit as problem solvers and a higher proportion of new adopters who traditionally take more risks at that time; our studies have shown that indeed high risk takers are less compliant with lens care.²⁷ If the number of daily disposable wearers grows to encompass the majority of full-time contact lens users, we hope that the rate of microbial keratitis will fall once again.

Delivery Vehicles
The topical application of therapeutic agents to the anterior surface of the eye is fraught with problems, including compliance (particularly in chronic conditions such as glaucoma), high clearance through tears and poor penetration of the drug through the cornea—meaning that doses are high, and local toxicity as well as systemic absorption can result.²⁸ Slow, regulated delivery through contact lenses would improve efficacy by decreasing the reliance on drug compliance and increasing the contact time, which would lead to lower levels of therapeutic agents, less toxicity and a reduction in systemic side effects.

Furthermore, contact lenses are already used as bandages for persistent epithelial defects and other ocular surface reconstruction. Amniotic membranes that contain numerous nutrients, such as growth factors, are used in recalcitrant cases.²⁹ It seems logical then that nutrients and healing agents could be incorporated in the contact lens material to slowly leach out over time; this, in turn, could speed up the healing process.
Over the past four decades, we have seen the introduction of several new techniques: incorporating barriers (e.g., vitamin E), molecular imprinting, particle encapsulation such as using liposomes, forming inclusion complexes and dissolving drugs in high-pressure volatile liquids such as carbon dioxide.²⁸ Particle encapsulation is a commercially used technique to deliver comfort additives in contact lenses.

Let’s concentrate on two promising technologies for therapeutic drug delivery: the incorporation of vitamin E as a barrier in contact lenses and molecular imprinting.

• Vitamin E barrier. Vitamin E, a hydrophobic liquid, is readily absorbed into soft lenses, including HEMA and silicone hydrogels, and forms aggregated bodies.²⁸ For hydrophilic drugs, such as timolol, vitamin E forms a diffusion barrier that slows down the release of the drug by forcing it to maneuver around the aggregates.

Conversely, hydrophobic drugs, such as dexamethasone, diffuse through the vitamin E bodies, which delays drug release. Silicone hydrogels have been more widely investigated because of their suitability for extended wear, a desired characteristic for maintained release of drug.
Drug diffusion in vitro studies show that, with around 35% vitamin E loading, timolol release is extended for 28 hours and dexamethasone for 150 hours (40x and 15x that of a standard lens, respectively).³⁰

Similar results have been found with fluconazole (hydrophilic antifungal), while longer release profiles occur with cyclosporine (hydrophobic immune suppressant) because it has a large molecular weight and high affinity for vitamin E.³¹ Less of a barrier is created with topical anesthetics because they adsorb and diffuse on the surface of vitamin E aggregates, and sustained release is only available for one day.

Timolol-loaded vitamin E lenses have been shown to lower IOP with minimal ocular surface disruption in a spontaneous glaucoma dog model; human clinical trials have not been conducted.³² Although the drug release profiles are promising, human in vivo release and drug toxicity need to be assessed. Furthermore, in vitro tests show a reduction in oxygen diffusion and, to a greater extent, lowering of ion permeability—a minimum amount of which is required for lens movement on the eye.³³ With cyclosporine, changes in the lens’s refractive index occurred during drug elution.³¹ Modeling of these changes indicates that sufficient oxygen, lens movement and vision stability will be available to have negligent clinical impact, but clinical trials are required.

• Molecular imprinting. During polymer synthesis, a macromolecular structure or memory for a drug template is created to form the molecular imprint. Drug release is governed by the size of spaces between the polymer chains, the drug molecule and drug/polymer interactions. Recent studies have indicated that the structure of the imprint, rather than drug itself, is predominantly responsible for the release profile; this indicates that the technique could be applied to a wide variety of small molecular weight drugs.²⁸ Furthermore, a therapeutic dose can be reloaded into the template, and lenses could then be worn both for daily use and extended wear.

An in vitro study using ketotifen fumarate—an antihistamine and mast cell stabilizer used for allergic eye disease—showed up to five-day release profiles with the conventional infinite sink method of diffusion measurement.³⁴ When the authors modeled a finite turnover condition similar to tear drainage and replenishment, they found that only 5% of the drug was released in five days compared to the infinite sink method.³⁴ This indicates that drug release may be sustained for longer than estimated from the conventional method, but this large variation needs to be confirmed in vivo.
Many low molecular weight hydrophilic drugs have been incorporated in molecular imprints, including timolol, norfloxacin and diclofenac sodium.³⁵ Recently, diclofenac sodium has been incorporated in a live or dynamic polymerase system that increases binding and delays release further.³⁶

High molecular weight molecules pose more of a challenge, but the comfort molecule hyaluronic acid (HA) has been incorporated in nelfilcon A and is available commercially as Focus Dailies with Aqua Comfort Plus (Alcon).³⁷ This technique used a biomimetic approach, using replications of an HA binding site in the molecular imprint to create higher affinity of HA with the lens.

Other in vivo work using molecular imprinted-contact lenses is limited; there is only one reported rabbit study using timolol-loaded lenses.³⁸ In vitro challenges such as changes to optical clarity, oxygen transport and mechanical properties in some networks have been reported.³⁸ Clearly, for promising molecular imprinted lenses, the next step should be in vivo testing of single and combination agents.

Contact lenses are primarily medical devices to correct refractive error while in situ. The extension of contact lenses as a device to prevent or slow down myopia and for use as a drug delivery vehicle broadens the population that may benefit from contact lens use. While comfort and vision are important considerations, the contact lens industry and eye care practitioners have a primary obligation to ensure lens safety is optimum, particularly for these possibly more vulnerable populations. 

Dr. Fiona Stapleton is the head of the School of Optometry and Vision Science at the University of New South Wales and senior research associate at the Brien Holden Vision Institute at the University of New South Wales, Syndey, Australia. Dr. Nicole Carnt is an optometrist and a National Health and Medical Research Council of Australia CJ Martin Biomedical Early Career Researcher at Moorfields Eye Hospital in London.

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