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It’s a story with stopgap solutions, but everyone is glued to a better goal—the creation of a transparent, soft and flexible ocular adhesive that can replace the need for sutures. However, the right product—one that is safe, effective, physician-friendly, patient-gentle and acceptably priced—has remained elusive, said David C. Ritterband, MD, clinical associate professor of ophthalmology at New York Medical College and assistant director of the cornea and refractive surgery service at New York Eye and Ear Infirmary.
“The environment is now ideal to develop a new adhesive for ophthalmic use,” said Terry Kim, MD, professor of ophthalmology and associate director of the cornea and external disease service at Duke University. “Cataract surgeries, corneal transplants, lacerations from trauma, leaking blebs—all could benefit from an adhesive application. And we could avoid some of the possible complications associated with suturing, such as infection, astigmatism and corneal neovascularization.”
Background on Ophthalmic Adhesives
Cyanoacrylate-based adhesives and fibrin glue are the most commonly used suture substitutes in ophthalmology, and both are used off-label in the United States, said David R. Hardten, MD, founding partner of Minnesota Eye Consultants in Minneapolis.
Fibrin is an old friend. Fibrin glue, now commonplace, was first created as a biologically derived adhesive almost a hundred years ago. It imitates the end of the coagulation cascade by adding thrombin to a solution of human fibrinogen. It is mass-produced from pools of human plasma.
Cyanoacrylates are newer. “Cyanoacrylate, also termed ‘crazy glue’ or ‘super glue,’ has been used for about 20 years for healing corneal perforations,” Dr. Hardten said. Dr. Ritterband was one of the first investigators to determine the feasibility and toxicity profile of 2-octyl cyanoacrylate as a temporary wound barrier in clear corneal cataract surgery. “Our research began after a discussion with my colleague Richard S. Koplin, MD,” Dr. Ritterband recalled. “He placed a drop of 2-octyl cyanoacrylate on his finger and remarked in passing that it may have the properties necessary to close the cornea.”
Cyanoacrylates, once used mainly in the management of corneal perforations and severe thinning, are compounds with very high tensile strength that rapidly polymerize on contact to form a strong bond, Dr. Ritterband said. Specifically formulated to correct some of the deficiencies of its predecessor compounds, 2-octyl cyanoacrylate avoids inflammatory reactions.
Standing on others’ shoulders. Dr. Ritterband was also inspired by the previous wound studies of Peter J. McDonnell, MD, now the chairman of ophthalmology at the Wilmer Eye Institute, who was among the first to put forth the notion of corneal wound vulnerability, challenging the assumption that hydration and stability with gentle manual pressure on the wound lip results in sufficient wound stability and watertightness for re-epithelialization to occur. Dr. McDonnell and his colleagues demonstrated corneal leakage with India ink applied to vertical incisions. “These experiments showed us that a clear corneal wound, when the eye is soft, is vulnerable to leakage,” Dr. Ritterband said.
From proving leaks to plugging them. “We decided to mimic these experiments, using the Miyake video system, laboratory models and India ink, to see if we placed glue on the wound whether it would prevent the ink particles from entering the wound,” Dr. Ritterband said. He and his colleagues did then show that the adhesive was indeed effective, confirming both the findings that clear corneal wounds were vulnerable to fluctuations in IOP or wound manipulation, and that using 2-octyl cyanoacrylate could prevent the influx of ocular surface fluid independent of IOP and manual wound manipulation.1
From this preliminary research, Dr. Ritterband and colleagues conducted an interventional case series on 51 eyes of 51 patients undergoing clear cornea cataract surgery. The standard 2.75-mm, clear corneal triplanar wound was dried with a weck-cel sponge, and two drops of 2-octyl cyanoacrylate were placed on a modified cellulose sponge and then applied in a small layer to the wound. The 2-octyl cyanoacrylate proved easy to apply, nontoxic and efficacious. He published the results, discussing the ease of applicability and a low side-effect profile.2
While cyanoacrylate has its benefits, it also has its drawbacks, Dr. Hardten pointed out. “The edges can be rough and sharp on the surface.” This hard, brittle substance tends to be uncomfortable and may require the patient to wear a bandage contact lens. “It’s strong and can seal corneal perforations, but it is not the ideal adhesive,” Dr. Hardten said.
Three Promising New Materials
Dr. Kim said new ophthalmic adhesives are a hot topic at both general ophthalmology and subspecialty meetings. Two new hydrogel agents are already approved in Europe and are now awaiting approval in the United States, and Dr. Kim is studying a novel class of substances.
OcuSeal Liquid Ocular Bandage, developed by HyperBranch Medical Technology, is intended for corneal, conjunctival and scleral surfaces. Dr. Kim said the OcuSeal Liquid Ocular Bandage consists of a synthetic hydrogel with a brush applicator. It forms a low-profile, smooth, soft and transparent barrier film on the ocular surface. “The indication is similar to a collagen corneal shield,” providing patient comfort in postsurgical and post-traumatic conditions, he said. “While it has been granted a fairly broad indication in the European market, it has yet to gain FDA approval here.”
ReSure Adherent Ocular Bandage, developed by Ocular Therapeutix, is a nontoxic, synthetic hydrogel bandage composed of 90 percent water and can be applied to the cornea, sclera or conjunctiva. The material is a liquid at first and then polymerizes in situ, forming a soft, protective barrier over the incision. The product remains on the ocular surface during normal re-epithelialization and then slowly sloughs off into the tears. It has the CE approval mark in Europe and was the subject of U.S. trials for which Dr. Hardten was an investigator. (ReSure used to be called the I-Therapeutix 1-Zip Adherent Ocular Bandage.)
Biodendrimers in birds’ eyes. Dr. Kim is now focused on the potential applications of biodendrimers, new single-molecular-weight polymer tissue sealants that might offer an alternative to cyanoacrylate glue. Using human eye bank specimens, he and his colleagues looked at the effects of biodendrimers on linear corneal incisions, stellate corneal incisions, clear corneal cataract incisions and LASIK flap incisions. They also recently conducted a study comparing sutures to dendritic polymer adhesives in the repair of central full-thickness 4.1-mm lacerations in the right eyes of 60 chickens. Half of the wounds were treated with biodendrimer polymer adhesive and half were closed with three 10-0 nylon sutures. The researchers conducted slit-lamp examinations at six hours, then daily for seven days and then weekly for 21 days. Scarring was more prominent at day seven in the glued corneas, but by day 28, the sutured corneas showed more inflammation and scarring and much more irregular anterior corneal surfaces. The researchers found that all the glued corneas remained clear while nearly all sutured corneas had some degree of corneal scarring through day 28. The sealant approach was also five times faster to finish than sutures.3 “We found less overlap of the Bowman’s layer with the adhesive and it probably induced less astigmatism,” Dr. Kim said.
A New World for Wound Closure
Dr. Kim believes the new biomaterials represent a major paradigm shift in wound closure in all surgical fields, moving away from sutures or staples and toward innovative ways to close a wound. And the eye is a great place to start. “The eye is a great model to study wound healing,” he said. “The cornea is so accessible as opposed to the inside of the body. And these products not only have the potential to replace sutures—they could also complement today’s other advances in technology in ophthalmic procedures.”
Dr. Ritterband agreed. “These new biomaterials not only promise to provide a nice coating for healing, but also may constitute a way to deliver antibiotics to the cornea without the need for eyedrops.” He would like to see large clinical studies of adhesives in the United States. And, should these materials receive FDA approval, he feels their pricing must make sense so they are economical to use.
1 Ritterband, D. C. et al. Am J Ophthalmol 2005;140(6):1039–1043.
2 Ritterband, D. C. et al. Ophthalmology 2005;112:2015–2022.
3 Kim, T. et al. Arch Ophthalmol 2009;127(4):442–447.
Dr. Kim reports consulting, grants and lecture fees from Alcon Surgical Devices and Ocular Therapeutix. Drs. Hardten and Ritterband report no related interests.