Currently, a number of new alternatives for corneal repair are under investigation. With that in mind, we spoke to several surgeons who deal with corneal wound repair on a daily basis, to find out why surgeons are anxious for new options and to get the lowdown on some of the new alternatives in the pipeline.

Sutures, Adhesives and Sealants

Francis S. Mah, MD, assistant professor at the University of Pittsburgh and director of the Cornea and Refractive Surgery Fellowship at the University of Pittsburgh Eye & Ear Institute, has tried many of the available approaches to corneal wound repair. “I think most ophthalmologists would agree that we need better ways to heal the cornea,” he says. “Sutures are still standard, but some of their problems are pretty obvious. You can’t see through a suture, so using one for a central corneal laceration interferes with vision. And because of the tension that sutures exert on tissue to pull it together, they may create irregular astigmatism. Also, unlike a sealant or glue which form a continuous bond, sutures are spaced apart. That creates a bond that’s weaker in some areas than others.”

A healthy human cornea with fluorescein dye under a slit lamp shows the presence of the new OcuSeal Ocular Bandage from HyperBranch Medical Technology. The polymer is highly biocompatible, transparent, and has a very low profile, causing little or no foreign body sensation. Human clinical trials are set to begin shortly. HyperBranch Medical Technology

Tisseal adhesive, a fibrin glue available from Baxter International, is a pro­duct used by many ophthalmologists. “Tisseal is frequently used with LASIK surgery flaps to prevent epi­thelial ingrowth, because sutures don’t create a continuous seal and can cause astigmatism,” notes Dr. Mah. “It’s also used for conjunctiva and pter­ygia repair, and amniotic mem­brane grafts. However, there’s a learning curve; you have to mix components and schedule several cases to­gether, and it can be costly. Also, it’s somewhat cloudy when applied, so corneal use can affect the patient’s vi­sion, although it does clear eventually.”

Some adhesive products originally intended for other uses have also been tried for corneal repair, notably Liquid Bandage (2-octyl cy­anoacrylate with parabens, Johnson & Johnson), which David Ritterband, MD, has investigated at the New York Eye and Ear Infirmary.^1,2 “Liquid Bandage seems to work pretty well,” says Dr. Mah. “The problem is that Liquid Bandage is similar to cyanoacrylate, which we often use in corneal surgery, particularly with perforations. Cy­ano­acrylates cause some pa­tients to experience a foreign body sensation, and some de­velop inflammation. The positive side is that we’re used to working with it. We know its history, and we know that it inhibits the growth of bacteria.

“The existing options are reasonably satisfactory,” he concludes. “But if we could come up with something that’s crystal clear, causes no inflammatory reaction, is user-friendly, is easy to apply and lasts a little longer, that would be great.”

Finding Alternatives

One of the most promising developments in this area is a new liquid hydrogel polymer developed at HyperBranch Medical Technology in Durham, N.C.; it should begin human clinical trials shortly. Terry Kim, MD, associate professor of ophthalmology at Duke University School of Medi­cine in Durham and Hyper­Branch’s consultant Chief Medical Officer, is one of the surgeons in­volved in its development. Dr. Kim’s pre­vious work in this field includes a 2004 study comparing a biodendrimer adhesive to conventional sutures for repairing corneal lacerations.³

A sutured corneal stellate laceration. These can be difficult to seal with sutures because of their irregular contours. Terry Kim, MD

Dr. Kim says the new polymer should help address the challenges of corneal wound repair. “Traumatic lacerations can generally be described as either linear or stellate,” he explains. “Sometimes a very clean, linear laceration, such as one that a piece of glass might cause, requires minimal or no suturing; a shelved linear laceration may self-seal with only a bandage contact lens placed over it. In contrast, a laceration produced by something with a jagged edge can cause an irregular, stellate wound; these almost always require surgical intervention.

“Obviously, we’re accustomed to repairing lacerations with sutures,” he continues. “Linear lacerations that need suturing usually just require a few suture bites, depending on the length. Stellate lacerations, however, are notoriously difficult to close, requiring multiple passes with multiple sutures. Sometimes the wound is so hard to reapproximate that putting a suture in one area causes a leak in another area; then when you suture that new leak, another area opens up.”

Dr. Kim adds that although surgeons still sometimes use cyanoacrylate adhesive to repair corneal wounds (an off-label use), a conventional cyanoacrylate adhesive isn’t ideal. “The material becomes stiff and opaque and can cause patient discomfort,” he says. “We often have to cover it with a bandage contact lens. You can’t see through it, so it’s hard to monitor wound healing or visualize the anterior chamber, and it can be toxic to the eye.”

In the 2004 study, Dr. Kim and fellow researchers demonstrated that biodendrimer adhesives could be a workable alternative to sutures. Enu­cleated human eyes received full-thickness incisions, which were then repaired using either sutures or the biodendrimer adhesive; once re­paired, the globes were pressurized with balanced salt solution to see how much pressure was required to cause wound leakage. For both linear and stellate incisions, either method was effective, but the resistance exhibited by the adhesive was significantly greater than that of the sutures. The study authors concluded that the use of biodendrimer adhesives to repair a corneal wound constitutes a viable alternative to conventional suture repair.

Creating the Perfect Polymer

Dr. Kim sees his current work with HyperBranch Medical Technology as expanding beyond this earlier work with biodendrimer adhesives. “Our goal at HyperBranch is to market a liquid hydrogel polymer based on a different dendritic chemistry that’s specifically tailored for ophthalmic use and can be put on the eye to act as an ocular bandage,” he says. “The new hydrogel polymer developed by Hy­perBranch is liquid when you deliver it, but within 30 seconds to a minute it polymerizes into a hydrogel that possesses the ideal properties for this use. It’s transparent; it’s flexible, so there’s some give to it; it has a very smooth, silicone-like texture, so you shouldn’t need a bandage contact lens on top of it; and it can be delivered in a very thin profile, to minimize the chance of dislodgement and patient discomfort.”

Anthony Sherbondy, president and CEO of Hy­perBranch Medical Technology, has been working with tissue adhesives and sealants for more than 10 years. “We’ve had a lot of experience with cyanoacrylates,” he notes. “They tend to have problems with biocompatibility, and their rough surface can abrade and irritate the eye. We know that ophthalmologists use them for corneal perforations and other conditions because there really isn’t an alternative product available.

“The material we’re working with is the flip side of that,” he says. “It’s soft and pliable and extremely biocompatible. Most of the eye-care professionals who’ve had the opportunity to manipulate it say it feels like it belongs on the eye. And it’s transparent, so it won’t obstruct visualization of the structures underlying the material; it acts almost like a bandage contact lens.”

Dr. Kim agrees. “One unique thing about this polymer is that you can apply as little or as much as you want,” he says. “I expect it will be supplied in a single-use applicator that you can use to wipe the polymer onto the wound. This will mean you can wipe the entire cornea if necessary, or just cover a single linear or stellate laceration. When you use a traditional bandage contact lens, you’re covering a large area for a wound that may be very small.”

‘Designer’ Adhesives and Sealants

Mr. Sherbondy says that one of the nice things about the hydrogel materials they’re working with is having the ability to alter their performance characteristics. “That makes it possible to give the material a cure time that’s convenient for the average ophthalmologist,” he explains. “In this case, we’ve designed our hydrogel material to set up within approximately 30 seconds so you can apply it and wrap up a case as quickly as possible. However, since we can alter the parameters of the material, we may eventually market different versions of it with different cure times or other characteristics, depending on their intended use.”

Mr. Sherbondy says the company has opted not to market biodendrimer adhesives that photo-polymerize when exposed to a particular frequency of light. “We deal with many conflicting design requirements, so there are trade-offs,” he notes. “It would be nice to control exactly when a material sets, as you can with photo-polymerizable biodendrimer adhesives, but this would require having another piece of equipment such as an argon laser in the OR. That would raise issues of cost and convenience. Also, biodendrimer adhesives don’t have other performance characteristics we believe are necessary in an ocular bandage for clinical use. We’ve optimized our hydrogel material for this particular indication, as a protective barrier in post-surgical, post-traumatic and non-traumatic ocular conditions.”

A new adhesive, tinted blue for easier visualization, coats the external third of an incision tunnel (right side of image). A chondroitin sulfate-based substance is placed on the wound, followed by a thin layer of polyvinyl alcohol covinylamine; polymerization into an adhesive occurs within seconds. Ashley Behrens, MD

Asked if it’s possible to adjust how long the polymer remains on the eye, he says that durability is another design criterion they’ve optimized in the hydrogel material, but durability is also a function of ocular surface conditions. “Physicians sometimes forget that they’re placing these materials on a biological substrate that’s constantly changing,” he says. “As the corneal epithelial cells slough off, these materials will also eventually slough off. So the length of time the polymer remains on the eye may be somewhat modulated by various factors, including the type of tissue and wound, the status of the surface epithelium, and perhaps other local environmental factors.”

Meeting Surgeons’ Needs

Dr. Kim says the new hydrogel polymer could potentially be used to bandage not only corneal lacerations, but any kind of surface abnormality: an exposed suture; an epithelial defect; a recurrent corneal erosion; and possibly even a cataract incision. ”Currently, the labeling for these types of products is fairly broad,” he notes. “Thus far, this product is described as a bandage for use in any kind of post-traumatic, post-inflammatory or post-surgical state, and to act as a protective barrier to increase patient comfort.

“I think a material with the right characteristics could have a lot of potential applications,” he continues. “There’s a lot of interest in creating a sutureless vitrectomy system, for ex­ample. A material like this might be able to seal pars plana sclerotomy incisions used in vitrectomy surgery and act as a bandage on the wound until it heals. It might also be able to seal a leaking filtering bleb following trabeculectomy. Other materials are often less than ideal for sealing a wound where the surface is epithelialized; some are quite expensive and involve lengthy preparation as well.”

Dr. Kim notes, however, that glues, including some fibrin sealants, can work very well in other surgical situations. “Some polymers that are less than ideal for corneal repairs can be highly effective when applied in an interface between tissues,” he says.

Mr. Sherbondy says he’s very pleased to finally be moving the new polymer towards widespread availability. “Despite considerable effort, no one has succeeded in coming out with the perfect material for use on the eye,” he notes. “I think we have something very close to that, and that’s what we’re planning to commercialize. This is a tool ophthalmologists have been looking for for a long time.”

According to Mr. Sherbondy, the company hopes to make the product available within the first half of 2007. HyperBranch is still planning to add additional clinical sites to the upcoming trial, so if your practice is interested in participating, you can contact him at anthonys@hyperbranch.com.

A square film of a new collagen-based, laser-activated tissue solder is placed over the cornea. After laser activation, it quickly melts. Within a few seconds it solidifies again, forming a smooth, gel-like shield over the tissue. Ashley Behrens, MD

Working with Chondroitin

Ashley Behrens, MD, assistant professor of ophthalmology at Wilmer Ophthalmological Institute in Bal­timore, has participated in several studies of adhesives for ophthalmic use. He’s currently testing the potential of two new adhesives for helping to seal corneal wounds—in particular, wounds created during cataract surgery—to address issues related to incision permeability and the development of endophthalmitis.

Dr. Behrens says the first of the two adhesives, developed by Jennifer H. Elisseeff, PhD, in the Department of Biomedical Engineering at Johns Hopkins University in Baltimore, is based on chondroitin sulfate (CS), a linear polysaccharide found in the extracellular matrix of tissues. When an aldehyde modification of CS is combined with polyvinyl alcohol co­vinylamine, adhesive properties are activated and polymerization occurs within seconds. (See picture, page 43.)

“Because chondroitin sulfate is a major component of most of the tissues of the body, including the cornea, we think it might be a very good option for use as a corneal adhesive,” he explains. Dr. Behrens notes that studies of CS-modified hydrogel in rabbit maxillary sinus mucosa found that it induced epithelial regeneration and served as a repository for cyto­kines and growth factors that promote wound healing.⁴ “This glue has also been used in preliminary trials in cartilage in vivo,” he adds. “In those ex­periments it was compatible with the surrounding tissue. We don’t ex­pect a major difference in the eye, in terms of tolerance or toxicity, but further in vivo experiments will tell us more.”

Dr. Behrens described the way the glue components are applied to treat a corneal wound. “First, we color the chondroitin sulfate with a special blue stain that will help us see exactly where this first component is on the corneal wound,” he explains. “Then we apply a thin layer that coats the surface of the incision and the external third of the tunnel, about 1.5 millimeters in from the wound edge. Of course, we take care not to get it into the anterior chamber, but that’s relatively easy when working with cataract surgery incisions. Next we apply a thin layer of the PVA compound and allow the two to polymerize for about 30 seconds. The mixture becomes gelatinous, really soft, like corneal tissue, so we don’t anticipate any discomfort for the patient.

“Essentially, we’re partly filling the wound rather than pulling the edges of the wound together,” he continues. “We’re sealing the lamellae of the collagen. Because the adhesive is bio­degradable, it tends to incorporate in­to the wound healing process, rather than interfering with it. It’s a very different approach from suturing. It acts like a matrix for regrowth of tissue and collagen.”

Early testing found the glue does a good job of sealing corneal wounds. In a study reported in 2005, Dr. Behrens and coworkers compared the intraocular pressure resistance of this glue to that of single and triple sutures.⁵ Using enucleated rabbit eyes, 3-mm clear corneal incisions were created, sealed with sutures or glue, and then subjected to increased IOPs. Mean leak pressure was 26.4 ±6 mmHg in the single-suture group, 44.3 ±8.2 mmHg in the three-suture group, and 101.4 ±3.2 mmHg in the glue group.

Dr. Behrens says they plan to begin live animal studies in the next few months. “We’ll be trying to determine biocompatibility, specifically for cor­neal applications,” he says. “And of course we have to determine what the permanence of the glue in the wound is. We’ll see if it’s digested or removed somehow by the wound-healing pro­cess.”

The Laser-Assisted Option

Dr. Behrens says the second glue he’s currently investigating is collagen-based and requires activation by a near-infrared laser after placement on the wound. This glue is under development by Conversion Energy En­terprises, a company based in New York. “When exposed to the la­ser, a thin film of this collagen immediately melts,” he explains. “As it melts, it creates a very smooth surface. Then within a few seconds it solidifies again, with the consistency of a gel.” (See picture, page 44.)

“In one test using rabbit corneas,” he continues, “we created central corneal wounds perpendicular to the surface of the cornea—full-depth wounds in the center. Then we took a thin patch of collagen, 2 or 3 mm square, and placed it over the wound and applied the laser. Within seconds after melting and gelling it was able to retain internal pressure up to levels five times normal IOP. Repairing a central wound of this kind using nylon sutures would take you a while, and would create the possibility of suture erosions and foreign body sensation for the patient.”

Dr. Behrens admits that having to use a laser could be seen as a downside. “As surgeons, we don’t want any more instruments inside the OR than necessary,” he says. “But everything has its pros and cons. The laser-activated glue might turn out to be better at holding in IOP than other alternatives. It might turn out to be more stable than the two-component glue. You can’t always have every useful characteristic in a single approach. The bottom line, of course, will be efficacy and what’s best for the patient.”

Moving Forward

Dr. Behrens says that both glues are reabsorbable. “That’s the beauty of them,” he says. “Stitches have to be re­moved a week or two later, meaning another visit for the patient and another anesthetic drop. These adhesives could prevent this.”

In addition, Dr. Behrens says both glues are basically clear. “We’ve been using a blue stain with the chondroitin sulfate in order to see the location of the glue in the corneal tunnel,” he says. “Primarily, we’ve been using both approaches to seal peripheral areas of the cornea, where transparency isn’t a major issue. Of course, it could be a problem if you’re trying to cover a wound in the center of the cornea, with the visual axis involved. That’s where we have to evaluate further for in vivo transparency.”

Dr. Behrens says the next step is to test the two adhesives in live animals. “We hope to start these tests using the chondroitin sulfate within a couple of weeks,” he says. “Because we haven’t done the in vivo studies yet, we don’t know what the behavior of the wound with the adhesive is going to be. We don’t know if astigmatism will be caused by contraction of the wound. We can’t guarantee that the optical quality will end up exactly the same as before the trauma or incision—at least not yet—but we hope that it will produce better outcomes than sutures. The good thing is that both adhesives have been used previously in other tissues, so we know they tend to be well-tolerated.

“It will be a while before we test in humans and go to the FDA,” he concludes. “In the meantime, both adhesives are in the process of FDA ap­proval for other applications. If they be­come available for those applications, ophthalmologists could consider using them off-label, once our trials have demonstrated their efficacy for use in the eye.”

1. Meskin SW, Ritterband DC, Shapiro DE, Kusmierczyk J, Schneider SS, Seedor JA, Koplin RS. Liquid bandage (2-octyl cyanoacrylate) as a temporary wound barrier in clear corneal cataract surgery. Ophthalmology 2005;112:2015-21.

2. Ritterband DC, Meskin SW, Shapiro DE, Kusmierczyk J, Seedor JA, Koplin RS. Laboratory model of tissue adhesive (2-octyl cyanoacrylate) in sealing clear corneal cataract wounds. Am J Ophthalmol 2005;140:1039-43

3. Velazquez AJ, Carnahan MA, Kristinsson J, Stinnett S, Grinstaff MW, Kim T. New dendritic adhesives for sutureless ophthalmic surgical procedures: In vitro studies of corneal laceration repair. Arch Ophthalmol 2004;122:867-70.

4. Gilbert ME, Kirker KR, Gray SD, et al. Chondroitin sulfate hydrogel and wound healing in rabbit maxillary sinus mucosa. Laryngoscope. 2004;114:1406–1409.

5. Reyes JM, Herretes S, et al. A modified chondroitin sulfate aldehyde adhesive for sealing corneal incisions. Invest Ophthalmol Vis Sci. 2005;46:1247-50.