Cornea
Advances in corneal transplantation devices

At a glance: Tranplantation devices

• Physicians prefer corneal grafts before implanting an artificial device
• In a tranplant recipient with no ocular surface disease, corneal grafts have 90% success rate
• For patients where condition of ocular surface would preclude human transplant tissue, artificial cornea is ideal solution
• OOKP is a viable alternative to artificial cornea in patients with devastating corneal disease

Technology improvements have improved the safety of artificial corneas, allowing those with little hope of functional vision the ability to see

Corneal blindness may affect up to 10 million people worldwide. In the United States, there were about 52,000 corneal transplants performed in 2008, of which 32,000 were full-thickness transplants, 17,000 were endothelial keratoplasty, 1,000 were anterior lamellar keratoplasty, and 173 were keratolimbal allografts, according to the Eye Bank Association of America. (The remaining transplants were tectonic, said Sadeer B. Hannush, M.D., assistant professor of ophthalmology, Jefferson Medical College, Philadelphia, and attending surgeon, Cornea Service, Wills Eye Institute, Philadelphia.)
With few exceptions, most specialists would prefer to attempt a corneal graft before implanting a completely artificial device. If—or more likely, when—the corneal graft fails, patients are left with the option of a second or third human corneal graft transplant or implantation of an artificial keratoprosthesis.
The Boston KPro (also called the Dohlman-Doane, developed at Massachusetts Eye and Ear Infirmary, Boston) was the first artificial cornea approved for use in the U.S. in 1992; the AlphaCor (Argus Biomedical, Australia) was approved in 2002. The KPro combines a donor cornea with manmade materials, but when fully assembled in the eye appears to be one piece, while the AlphaCor is a curved plastic disc where the central part is clear; the implantation is a two-part procedure where the patient’s tissue covers the implant for a short time.

Corneal transplantation

Corneal transplants have a history spanning back more than 200 years, said Mark J. Mannis, M.D., professor and chair, Department of Ophthalmology, University of California, Davis, Eye Center, Sacramento, Calif. The primary treatment involves creating (or maintaining) a favorable environment for subsequent transplantation, said James V. Aquavella, M.D., professor of ophthalmology, University of Rochester Eye Institute, Rochester, N.Y.
When using a patient’s own cells, biocompatibility is not an issue, and immunosuppressant drugs are unnecessary. But autografts can be successful only if a single eye is involved in the initial disease. With donor grafts, however, patients will need immunosuppressants and vision rehabilitation can take up to a year.
Stem cell transplantation is typically used as a first-line treatment for conditions such as aniridia, or poor epithelial quantities, where traditional corneal grafting has failed, Dr. Hannush said.
Stem cell transplantation “would certainly be a great option” but the procedure is methodically complicated, said Sophie Holak, M.D., Eye Department, Schlosspark-Klinik Charité University Berlin, Berlin.
“If you can find a source of stem cells from a patient himself, the possibility of rejection is zero,” Dr. Hannush said.




Source: Donald T.H. Tan, F.R.C.Ophth.

“The disease is often present in both eyes, or even if present in one there may be reluctance on the part of the patient to invade the ‘other healthy eye’,” Dr. Aquavella said. “The necessity for immunosuppressants associated with the use of donor cell transplants, combined with the long time required to complete the process of surface followed by whole cornea transplants, and the questionable long term results is a problem for me. I no longer use this methodology, and rely on keratoprosthesis which produces rapid visual rehabilitation.”
The number of corneal transplants was declining until the introduction of endothelial keratoplasty (EK), said Edward J. Holland, M.D., professor of ophthalmology, University of Cincinnati, and director, Cornea Service, Cincinnati Eye Institute. During the 1980s, the increase in penetrating keratoplasty (PK) was due to the higher rates of pseudophakic corneal edema, he said. As the IOL technology and phaco techniques improved, the indications for corneal transplants for psudophakic corneal edema decreased, he said. However other conditions with endothelial failure were still significant. The decision to intervene surgically was often delayed until advanced visual loss due the problems associated with PKs.
“Now with the great success we’ve had with EK, we can recommend surgery for other conditions such as Fuchs’ Dystropy much earlier; as a result transplantation rates are increasing again,” he said.
In a “normal” recipient—those with no underlying ocular surface disease or limbal stem cell failure—corneal grafts have a 90% success rate in the first year and about 70% success rate over 10 years, said Esen K. Akpek, M.D., associate professor of ophthalmology, and director, Ocular Surface Diseases and Dry Eye Clinic, Wilmer Eye Institute, Johns Hopkins University, Baltimore. She added previous corneal graft failure puts patients at a higher risk for subsequent failure.
“The first graft has a 90% chance of success, the second 50%, and the third only 20%,” she said, adding she’s yet to perform more than three graft transplants on any one patient.
The “ideal” candidate for an artificial cornea are those “the ocular surface of the recipient would not allow human transplant tissue to survive—autoimmune diseases, chemical burns or severe dry eye,” Dr. Mannis said. “For most patients, though, a keratoprosthesis is an operation of last resort.”
Dr. Akpek added aphakic children may also benefit from primary keratoprosthesis implantation in lieu of corneal grafting.

Artificial corneas

Keratoprostheses should be used in three situations, Dr. Holland said: if the patient is at an immunologic high risk of graft failure, in severe ocular surface disease, and in cases where endothelial failure is high. It’s a law of diminishing returns, Dr. Hannush said.
“Repeat transplants have a lower and lower success rate, so the question must become: How many times do you re-graft before you opt for an artificial cornea?” he said.
Keratoprostheses have some advantages, among them the minimally invasive surgery and intralamellar position, Dr. Holak said. But they are not without potential problems, including stromal melting, she said.
“The keratoprostheses are not used more often because they are still associated with significant complications that will require ongoing follow-up for the rest of the patient’s life,” Dr. Mannis said. In a recent UC Davis study, one of the biggest complications was secondary glaucoma, he said. “Once the keratoprosthesis is in, there’s no accurate way of measuring intraocular pressure,” Dr. Mannis said. “You’re left with tactile tension measurements, which are not the ideal method.”
Somewhere between 30% and 50% of all patients implanted with the KPro develop retroprosthetic membrane (RPM), Dr. Holland said. Some of the RPM can be removed by a YAG, but in some cases a a pars plana vitectomy and membranectomy is needed. Very few patients who develop RPM will go onto develop severe vascularization, Dr. Akpek added.
Long-term, low grade inflammation from the PMMA material most likely causes the RPM, Dr. Aquavella said. The latest iteration of the KPro uses titanium on its back plate, which should reduce the incidence of RPM, he added.
“It’s a wonderful device in the right patient, but in no way should it be the primary device,” Dr. Holland said. “If the corneal transplant has failed, especially in a younger patient, I’d opt for a second graft rather than the KPro.”
Dr. Akpek seconded this, “I don’t think the KPro is the ideal device – yet. But it is the best that exists.”
In the U.S., the AlphaCor has fallen out of favor, “due to its poor visual results, difficulty of surgical technique, staged surgery, and limited indications. I know of no program still working with this prosthesis,” Dr. Aquavella said.
The KPro “is very easy to implant,” Dr. Mannis said, while other alternatives—such as osteo-odonto-keratoprosthesis (OOKP) require a totally different set of skills.
Even though the KPro is considered a “last resort” there are contraindications, said Donald T.H. Tan, F.R.C.Ophth., head and senior consultant, Singapore National Eye Centre, Singapore. For instance, patients without eyelids or with extremely poor ocular surfaces will not gain any benefit from these kinds of artificial corneas, which is when the OOKP type of procedure can be advocated, he said. Dr. Hannush added OOKP should be considered for patients with severe Stevens-Johnson syndrome, herpes, or ocular cicatricial pemphigoid.

Alternative artificial corneas

The OOKP procedure can be successful, with upwards of 50% of patients having 20/20 vision and 60% having 20/40 vision, Dr. Tan said. But it is “quite major surgery, with two operations spaced 2 to 3 months apart,” he added.
Once the decision to perform OOKP is made, there’s no turning back, either. If it fails, there is no redress, Dr. Tan said. “We’ve had tremendous success, the eye is so stable after surgery patients are able to see very well for the long term,” Dr. Tan said. “Patient are off almost all eye drops, and no immunosuppression drugs are needed.”
To perform OOKP, the surgeon first removes the canine tooth from the patient and shaves the root down to form a base to embed a PMMA plastic optical cylinder, about 4mm in diameter, Dr. Tan said. The surgeon then places the optical cylinder back in the cheek muscle of the patient, where it stays in place for about two months. “The tissue is still alive, and that’s a key issue,” he said. “It regains the blood supply.” After the two months, the device is removed from the cheek and implanted in the cornea, covering the entire buccal muscosal from the cheek, over the entire cornea and scleral area. During the second stage, the tooth is embedded under this buccal muscosal graft and a hole is cut in the graft to allow the patient vision.
“The results are quite stunning,” he said; in his 30 cases, there have been no extrusions. Compared to the KPro, time to final vision is a little longer—four weeks compared to about seven days. Because the implantation involves removing the iris and any lens or implants, the vitrectomy tends to leave some blood in the vitreous cavity; once that’s cleared, the patients reach full visual potential.
The initial OOKP technique described by Strampelli and modified by Falcinelli showed “long-term results with 2% loss of the prosthesis over 27 years,” Dr. Holak said. She cited the postoperative cosmetic outcome as a potential disadvantage as well.
OOKP is a viable alternative to the artificial cornea, but should be considered only for devastating corneal diseases or horrible chemical burns/accidents, Dr. Aquavella said.
“It’s a multi-staged, very difficult technology and operation and once the device is in place, re-operation is complicated if not impossible; bone absorption is an ongoing problem that requires multiple MRIs to monitor,” he said.
In order for patients to have the OOKP procedure, they also need to have a dental assessment, and in some cases the oral mucosa may be too damaged. Patients who smoke should be advised to stop smoking to improve the chances of revascularization. And there needs to be adequate space between the teeth so that harvesting one does not damage surrounding tissues or teeth.

Future transplantation techniques/devices

Although long term results have not yet been achieved, the titanium backing of the KPro seems to have good initial results—and a much reduced RPM occurrence, Dr. Aquavella said.
Down the road, “I envision the Boston device being used in more and more cases which have been considered for OOKP. Clearly, there is still much work to be done to improve the results in highly inflamed autoimmune diseased eyes,” he said.
In the long term, he said he believes replicating and re-growing a cornea in the lab is where the industry is heading, and most others agree. Most cite the work of May Griffith, Ph.D., Ottawa Hospital Research Institute, Ottawa. She and her researchers have developed “the world’s first functional human cornea based on cell lines for in vitro toxicology use,” according to the institute. She and her team have more recently developed a “range of biointeractive, biomimetic corneal substitutes that have been successfully tested in animals,” the group said on its Web site.
“We can’t guess how long that will take to be viable in humans, and I don’t think it will eliminate need for corneal transplantation worldwide, but will help in third world countries where clear corneal tissue is hard to come by,” Dr. Aquavella said.
Dr. Hannush said the “greatest advance” in recent years has been “selective keratoplasty”—techniques such as EK for conditions like Fuch’s dystrophy are responsible for 33% of all transplants, he said. In his practice, 75% of the transplants performed last year were EK. “In 10 years, we’ll have the ability to culture a cornea in the lab, possibly through genetic engineering,” he said.
Dr. Akpek and her team are working on synthetic materials to create an artificial cornea that can replace the need for donor tissue. In the interim, she has a paper in press discussing the visual outcomes of the KPro—with zero refractive error on day 1 post-op.
“We’ve been able to achieve 20/20 uncorrected visual acuity the day after surgery,” she said. The main advantage of the KPro, she said, is that its rigid center eliminates induced astigmatism and it can be adjusted based on axial length.
“If we could have a material that’s PMMA in the middle and highly biointegrated, that would be ideal,” she said. In her opinion, artificial corneas will eventually replace donor corneas altogether, especially in countries where tissue quality is not optimal.
“We are heading towards a bioconstructed cornea,” Dr. Mannis said. “It’s still very preliminary, but researchers will come up with one that can supplant both the KPro and OOKP.” He cautioned that wherever research takes the field, cornea specialists will still need to manage the surrounding ocular surface.
Dr. Tan is working on a completely artificial implantation for the OOKP procedure, bypassing the need for a donor tooth. Although he’s working on using polymers that have shown good biocompatibility in other transplant surgeries, “it’s not anywhere near development stages yet.”
“The next two decades will be the era of significant development in treating corneal diseases,” Dr. Tan said. “For many years, we’ve had penetrating keratoplasty. Now with all the new technologies, tissue engineering, tissue culture, etc., we’re making huge advances and making the whole procedure more accurate.”
In his opinion, the “ultimate breakthrough will be our ability to culture tissue conjunctiva,” Dr. Holland said. “We do a pretty good job already with pure limbal deficiency, but cultured conjunctival replacement is where we’re focusing.”

Editor’s note: None of the physicians mentioned have financial interests related to their comments.

Contact information:

Akpek: 410-955-5214, esakpek@jhmi.edu
Aquavella: 585-275-8944, James_Aquavella@URMC.Rochester.edu
Hannush: 215-752-8564, sbhannush@comcast.net
Holak: +49 0 5341 49433, so.holak@gmx.de
Holland: 859-331-9000, eholland@fuse.net
Mannis: 916-734-6957, mjmannis@ucdavis.edu
Tan: +85 6227 7255, snecdt@pacific.net.sg