Where have all the smart lenses gone, long time passing; Where have all the smart lenses gone, long time ago?

It has been more than a decade since publications reported the advent of smart contact lenses.¹ The passage of time without commercialization of component-containing lenses begs several questions. Perhaps the most critical is: Why is the time for commercialization so long? The short answer: Because it is difficult.

Smart contact lenses are a road less traveled, and much like the first three words in M. Scott Peck’s book, The Road Less Traveled, “Life is difficult.” To take a great lesson from the world of emerging technology: products must be useful, and they must be usable.

USEFUL IS RELATIVE

First, a smart contact lens must be useful. It must provide a better solution than would a less complicated or less invasive method of doing the same. Even then, good is the enemy of best, so an adequate option may continue to capture market share as an alternative to a smart contact lens option that may, in some ways, be better. Those developing a smart contact lens platform must maintain confidence that the device is highly useful.

Strong cases can be made for the usefulness of drug delivery smart contact lenses and of contact lenses that sense biological markers, microbiological markers, biochemical markers, and physiological patterns. Contact lenses for photobiomodulation can be rationalized. Accommodating smart lenses for presbyopia may solve a long-standing need that has not been fully met with monovision or with multifocal contact lenses. Smart contact lenses for extended reality (XR) may provide higher performance in more stylish display eyewear or may eliminate the need for display eyewear altogether.

The realm of XR that includes augmented reality (AR), mixed reality (MR), and virtual reality (VR) may have questionable usefulness until it is better understood or until it is experienced by patients, workers, and consumers. Even so, more than $4 billion has been spent in the pursuit of suitable XR systems over the last 20 years, and an increasing amount is directed toward smart contact lenses for XR.² In the end, the market will determine the relative benefit and usefulness of smart contact lens XR applications over the display eyewear systems that do not employ a contact lens.

Two products generally classified as smart contact lenses gained U.S. Food and Drug Administration (FDA) market clearance. The first is a light-adapting lens that is now commercially available.³ Another device that has FDA clearance as a Class II device is cleared as a diurnal pattern recorder system and has an encapsulated strain gauge and electronics to provide an analog of intraocular pressure (IOP) as an adjunct to tonometry. It is noteworthy that the FDA does not classify that device as a contact lens; therefore, its material did not require a United States Adopted Name (USAN).⁴ The device is worn on the eye when open and closed for a single use of up to 24 hours. Both of the aforementioned products are at the stage of consumers and practitioners determining whether these devices are useful over traditional and contemporary alternatives for managing ambient light or monitoring diurnal IOP, respectively.

There is a regulatory element to being useful as well. Most smart contact lenses are in a first-through-the-door position and have no predicate contact lens. The indications for these smart contact lenses are expected to be new indications. The sponsor (i.e., the party commercializing the technology), in conjunction with regulatory agencies such as the FDA, must determine a new indication for labeling the smart contact lens. The indication will state the intended use of the product, and the clinical evaluation must support that the smart lens fulfills the stated indication; this is a part of the realm of efficacy. Even when efficacy is supported by clinical evaluation, the relative usefulness to eyecare professionals and to consumers is highly significant and reflects in the final commercial outcome.

USABLE IS ABSOLUTE

Beyond being useful, a smart contact lens must be usable or suitable for use. Two subsets of being usable are safety and consumer-friendliness. Because smart contact lenses are medical devices, they must demonstrate a safety profile acceptable to regulatory agencies and their respective advisory panels comprised of industry experts and consumer advocates. The safety profile of a smart contact lens is determined during the phases of clinical and regulatory development.

A smart contact lens’ physical and chemical properties are identified and measured, and toxicology tests are completed as part of a biocompatibility assessment. The material and the components of a smart contact lens must demonstrate that they fall in acceptable ranges for cytotoxicity, systemic toxicity in vitro and in vivo, and ocular irritation when worn for 21 days by New Zealand white rabbits. The first in vivo performance may be demonstrated with animal testing as well.

Smart lenses that have electronic components and electromagnetic radiation emissions are expected to require biocompatibility testing beyond what is required by the guidelines for standard daily and extended wear contact lenses. New contact lens materials will be developed as part of the emerging smart lens era. Each new lens material will require a USAN. The USAN is required for the lens substrate alone, and the substrate with the integrated or encapsulated components or pharmaceuticals could require a USAN with an extension or modifier.

Care product compatibility must also be demonstrated for novel materials and for lenses that contain components. Keep in mind that contact lens materials that are oxygen-permeable are also water-vapor-permeable and capable of uptake of other molecules based on the chemical composition of the lens material and the methods of inclusion of the components. The ability of oxygen or water to impact the lens components and their performance must be evaluated. It is noteworthy that H₂O is a smaller molecule compared to O₂; hence, water-vapor permeability is generally greater than oxygen permeability is for a given material.⁵ Water-vapor transmissibility is a significant factor when electronic components reside within a lens. Evaluating the impact of water on any components may be required by a new protocol for shelf-life testing.

Lens materials may also take up chemicals in care products by surface binding or into the material matrix. A primary concern is preservative uptake. Furthermore, any chemicals that are taken up have the potential to be released during contact lens wear. Therefore, preservative uptake and elution testing are a part of the care product compatibility testing for new materials and for component-containing contact lenses manufactured by multistage molding or assembly of lens parts in which adhesives are used and in which seams or joints are present.

Lenses that are pre-loaded with pharmaceuticals present new problems concerning shelf life. Exposure of the lens package to light and to other conditions that could degrade or change a pharmaceutical may require new guidelines for determining product stability and shelf life.

Usability in terms of consumer friendliness encompasses practical usability such as ease of lens application and removal, care product requirements, replacement modality, cost and convenience of use, and impact on life quality. The impact on a patient’s quality of life includes comfortable wearing time; user appearance when wearing the smart lens; clarity of vision and visual noise, which includes glare, halos, starbursts, and impact on vision of bright light or darkness; and comfort of the eyes and refractive changes upon lens removal. Does a lens have any downsides even if it is useful beyond conventional means of achieving the same purpose?

Most of us have learned that reality means compromise and that we must often accept some negative elements of almost anything to enjoy the greater positive. Usable and useful are not mutually exclusive in this regard. Regulatory bodies and advisory panels weigh the complications and risks captured during the clinical evaluation phases in the context of the benefits with a new device to determine final clearance and to stipulate the required language in the labeling to fully inform prospective users.

ON THE HORIZON OR IN REACH?

There is a substantial body of patents issued and pending for smart contact lenses. These filings include contact lenses for drug delivery, for active refractive power change for presbyopia, for XR, for lenses that have electronic and non-electronic means of sensing ocular physiology, anatomy, and biochemistry, and for therapeutic use. The patent filings, along with press releases and journal articles, tell us what is on the horizon. However, the horizon is like a rainbow; you can see it while not being able to reach it. The relevant question is: What smart lenses have moved from the horizon to be within reach?

Some developers choose to remain stealthy and may be much further along than is publicly known beyond their published patent filings. Other developers have a high media presence while remaining years from the market (especially given how difficult and multifaceted the development process may be). One marker for progress and perhaps being in reach is the posting of clinical studies on ClinicalTrials.gov , which is maintained by the National Library of Medicine (NLM) at the National Institutes of Health (NIH).⁶ The pertinent regulation amended in 2007 requires the reporting of a prospective clinical study of health outcomes in human subjects that compare an intervention with a device against a control device. The exception is small clinical trials to determine a device’s feasibility or a clinical trial to test prototype devices in which the primary outcome measure relates to feasibility and not to health outcomes.⁷ The intention is to ensure public disclosure of studies that contribute to new devices’ safety profile.

Publication of results from clinical trials in peer-reviewed journals can be another marker for movement from the horizon to being in reach. Many peer-reviewed journals require that the clinical trials that are the subject of an article be reported on ClinicalTrials.gov . Keep in mind that in-reach is like seeing a mountain top behind a closer mountain. You can see the second mountain top without really knowing the length of the valley between the two mountains. You know only that you can likely get to the second mountain while not knowing the distance or time to get there.

Drug Delivery Smart Lenses in Reach  Drug delivery smart lenses (Figure 1) appear to be in reach while having been on the horizon for a long time. The advantages of delivering a uniform dose of a medication over time while also managing patient noncompliance with topical ophthalmic medications are well understood. The targeted diseases for smart lens drug delivery include glaucoma, microbial keratitis, and allergy in conjunction with lens wear; more recently, drug delivery lenses are also targeted for reducing inflammatory retinal vascular leakage.

Clinical trials have been conducted for timolol maleate and dorzolamide hydrochloride, with vitamin E ((+) α-tocopherol) as an additive for achieving extended release of the drugs for the management of glaucoma, and for latanoprost by another mechanism for the management of glaucoma.^8,9 Additional studies report the use of the contact lens material etafilcon A combined with a small amount of the antihistamine ketotifen as an anti-allergy agent.¹⁰ In addition, the timed release of dexamethasone from a contact lens for managing retinal vascular leakage is presented in a recent ClinicalTrials.gov posting.¹¹

Sensing and Imaging  More than a decade ago, one smart lens technology report described a method for sensing an analog to blood glucose level.¹² While patent filings are published and, in some cases, issued for electronic technologies within the lens for sensing, reports of pivotal phase 3 clinical trials are not apparent. Devices and methods for passive sensing of blood glucose level analogs have also been reported, yet without reports of clinical activity.^13,14 It is understandable that it is possible to sense other biochemical markers, including inflammatory mediators and tear osmolarity, with a future lab on a lens.

The diurnal IOP monitoring device mentioned earlier has a rich history of clinical activity as a single-use product for reporting an analog to IOP during open- and closed-eye wear for up to 24 hours.¹⁵ The product is the first and only FDA-cleared device to encapsulate microelectromechanical systems (MEMS) in a contact lens-like substrate. The substrate material is reported to be polydimethylsiloxane, a silicone elastomer.¹⁶

Examples of on-the-horizon smart contact lenses for imaging include patent filings for contact lenses that have encapsulated posterior-facing cameras for imaging the internal eye.^17,18 A posterior-facing camera could have utility for gonioscopy for monitoring angle closure, monitoring pupil reactivity, iris pattern recognition for security systems and identification, and for posterior chamber monitoring.

A recent publication announced an on-the-horizon smart contact lens designed for full-corneal electroretinogram signaling. At Peking University, Beijing, scientists have demonstrated soft, transparent graphene contact lens electrodes (GRACE) for conformal full-cornea electroretinogram signal recording in rabbits and cynomolgus monkeys.¹⁹ There is considerable technology development underway with the joint effort of encapsulating MEMS in soft contact lenses.

Forbes reported a collaboration between two companies to develop smart contact lenses that include electronics in a hydrogel substrate. Applications appear to include health-related use cases as well as the mention of autofocus capability and XR.^20,21

Accommodating Contact Lenses for Presbyopia  The largest single body of filed patents teaches the components, methods, and systems for manufacturing accommodating contact lenses. One company discussed the advent of its novel product for presbyopia²¹ (Figure 2). Patent filings by other parties developing accommodating smart contact lenses are also published. These technologies represent very advanced smart contact lenses and their elegant systems for communicating a wearer’s need to change focus to the accommodating element within the lens. A search of the literature and clinical activity leaves uncertainty as to whether an accommodating contact lens product is in reach or on the horizon only.

Extended Reality  At least two approaches are in development for XR that include smart contact lenses as part of the system. One developer conducted off-the-eye demonstrations earlier this year of its monochromatic light-emitting technology that is intended to be incorporated into a scleral lens platform (Figure 3A). Its patent filings teach more than one method of producing an in-the-contact-lens technology that delivers images on the retina of a user’s eye. The scleral contact lens includes power sources, processors, eye-tracking gyro sensors, and, in one case, a plurality of femto-projectors that are intended to direct the light to the retina to form the images.^22,23

An additional patent filing teaches that there is a cavity behind the components to receive oxygen from the anterior surface of the lens and from which the oxygen will then transfer to the post-lens tear film through the posterior layer of the lens.²⁴ The oxygen delivery system is similar to the methods used in a folded reflective optic scleral contact lens developed by the University of California, San Diego in the past. The display scleral contact lens and the telescopic scleral contact lens are reported to require a thickness of greater than 1mm and include non-GP components.²⁴ The scleral display smart contact lenses are expected to require an external appliance for managing data transfer and electrical power for the onboard electronics. Another patent filing provides a spectacle frame format for the external appliance²⁵ (Figure 3B).

The second XR smart contact lens serves as an optical solution to eliminate the optics from display eyewear and, thereby, assist display eyewear developers in making their products more usable by decreasing the bulk and weight and increasing the field of view and resolution.²⁶ This smart contact lens has a two-state light polarizing filter and a microlens to focus the display light in the spectacle plane. The outer filter blocks the display light passing through the refractive error correction zone of the lens. The central microlens and inner filter focus and pass the display light while attenuating the ambient light²⁷(Figure 4).

The prevalence of those needing refractive correction and the age demographics of those expected to adopt XR when applications become available support positive future demand for conventional disposable contact lenses to eliminate the need to wear spectacle eyewear behind the display eyewear and for the opportunity to wear XR smart contact lenses.

Photobiomodulation and Other Therapeutic Smart Contact Lenses  Light-source-containing smart contact lenses were first described in patent filings for seasonal affective disorder and outdoor light replacement for myopia regulation.^28,29 The light sources include microscale light emitting diodes (LEDs), including quantum dot LEDs. More recent indications using the same concepts with photonic variation include near-infrared light for diabetic macular edema. A clinical trial is studying near-infrared photobiomodulation, with a laser light source having a 4mm to 5mm beam.³⁰ Future incorporation of the light source into a contact lens is envisioned. Other researchers have discovered the possible value of infrared light in reducing the progression of age-related macular degeneration.³¹

Smart lenses for therapeutic use containing novel MEMS systems may be in reach. One smart lens includes a gold coil activated by components in a spectacle frame to innervate the coil to deliver transcorneal electrical stimulation that targets the eye’s aqueous inflow and outflow structures to reduce IOP to manage glaucoma.³²

Another smart contact lens is aiming to manage corneal melting. A common poly(2-hydroxyethyl methacrylate) (pHEMA) material backbone is combined with dipicolylamine (DPA), which has a high affinity for and selectivity toward zinc ions. As a result, the DPA-conjugated pHEMA hydrogel in animal studies selectively removes zinc ions from a physiological buffer and effectively prevented degradation of porcine corneas by collagenase A, a zinc-dependent protease. The presence of pDPA-HEMA hydrogel did not affect the viability of keratocytes or corneal epithelial cells.³³

Researchers at the University of Liverpool reported results with a nitric oxide (NO)-releasing contact lens gel displaying broad-spectrum antimicrobial activity against two of the most common causative pathogens of microbial keratitis. The contact lens gel is composed of poly-ε-lysine functionalized with NO-releasing diazeniumdiolate moieties, which enables the controlled and sustained release of bactericidal concentrations of NO at a physiological pH over a period of 15 hours. The bactericidal efficacy against Pseudomonas aeruginosa and Staphylococcus aureus was ascertained, and between 1 log and 4 log reductions in bacterial populations were observed over 24 hours. Additional cell cytotoxicity studies with human corneal epithelial cells also demonstrated that the contact lens gels were not cytotoxic, suggesting that the developed technology could be a viable alternative treatment for microbial keratitis.³⁴

MONITORING THE PATH TO MARKET

As clinicians, our greatest interest is in products available today to enable us to help our patients in the here and now. The early reports of smart lens technology were clearly too optimistic with regard to the time frame for commercialization. The undesired consequence is unfulfilled expectations. Smart lens development is challenging, multifaceted, and has taken longer than the expected forecast. Even so, technology continues to develop at a pace that suggests that envisioned and patented smart contact lenses are moving from being “on the horizon” to being “in reach.” CLS

REFERENCES

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