This article is more than 5 years old. Information may no longer be current.
Innovations edge nearer to meeting global demand for corneal transplantations
Click Here to Manage Email Alerts
For about 50 years, corneal transplantation was synonymous with full-thickness grafts. For every corneal disease, whether it was stromal scarring or endothelial failure, the answer was penetrating keratoplasty. Since the turn of the century, lamellar surgery has heralded a revolutionary shift toward replacing the diseased layer rather than the entire cornea.
“Innovation has resulted in improved lamellar surgery. We no longer are performing penetrating keratoplasty for all corneal transplants. The goal is to replace the abnormal layer and leave the normal corneal layers intact. What has evolved is ocular surface transplants for conjunctival and limbal deficiency, DALK for stromal disease and endothelial keratoplasty for endothelial disease. This surgical strategy has improved surgical outcomes tremendously,” OSN Cornea/External Disease Board Member Edward J. Holland, MD, said.
From thinner graft to no graft, corneal regeneration and cell transplantation are now the new frontiers for treating corneal disease, with several successful attempts being made in both the posterior cornea and anterior cornea.
As well, recent advances in the design of artificial corneas are poised to overcome previous limitations and promise to offer alternative solutions to the worldwide shortage of donor tissue.
Source: Edward J. Holland, MD
“Thirty million people are waiting for a corneal transplant worldwide, most of them in the developing world. The way we currently do eye banking is not sustainable. We have to be creative in how we solve the problem, and both corneal regeneration and artificial corneas are opportunities we must pursue,” Holland said.
Evolution of endothelial graft surgery
When Descemet’s stripping automated endothelial keratoplasty was first introduced, grafts were as thick as 180 µm to 200 µm. Improvements progressively reduced tissue thickness, leading to better anatomic and visual outcomes.
Holland has hypothesized a correlation between thinner grafts and better vision. He and colleagues recently published in Cornea the results of a technique for nano-thin DSAEK, which showed that DSAEK grafts of 50 µm or less lead to visual outcomes comparable to those achieved with Descemet’s membrane endothelial keratoplasty.
“The general trend has been toward using thinner and thinner tissue, and DSAEK has become ultra-thin DSAEK, with grafts of less than 100 µm, or nano-thin DSAEK, with grafts of less than 50 µm,” OSN Cornea/External Disease Board Member Terry Kim, MD, said.
DMEK has been a further improvement in this regard. Because only the Descemet’s membrane and the endothelium are implanted, thickness is typically about 15 µm. Pre-Descemet’s endothelial keratoplasty, which also harvests the pre-Descemet’s layer, is somewhere between DMEK and DSAEK, with graft thickness of about 30 µm.
DSAEK is relatively easier than DMEK, which accounts for why it has been more easily and widely integrated into U.S. surgical practice and why some surgeons are still reluctant to switch to DMEK.
“DMEK is more closely associated with what you are removing, so it is better anatomically and visually as shown by the literature. The procedure, depending on how your donor tissue is prepared, can be as quick as DSAEK, but there is a learning curve because the thin and delicate tissue can be difficult to manage, and it can unfold in an unpredictable fashion. DSAEK has been around longer, and tissue manipulation is more predictable. There are devices that can assist you, such as the EndoSerter (CorneaGen) and the Busin Glide (Moria). The other advantage of this procedure is in complex eyes, where it is more predictable and associated with fewer complications,” Kim said.
In a paper published in the Journal of Cataract and Refractive Surgery, Kim and Wei-Boon Khor, FRCS, FAMS, showed that DSAEK with the use of the EndoSerter for injection was especially suitable for high-risk or complex eyes after trabeculectomy, glaucoma tube shunts, anterior chamber IOLs and previous corneal transplant surgery.
“Those are the cases where it is more difficult to perform a DMEK procedure. Surgeons who do both tend to stratify their cases and treat normal eyes with DMEK and high-risk or complex cases with DSAEK,” Kim said.
The advances in DMEK are related to donor tissue preparation. Originally, DMEK grafts were prepared by the surgeon at the time of each procedure. The donor tissue was cut, and the Descemet’s membrane was manually peeled and then stained with trypan blue. The risk for damaging or contaminating the tissue accompanied each step. More recently, eye bank-prepared grafts have become available. The first generation was to prepare pre-stripped membranes, trephined to a preset diameter, and then placed in storage media in a tube. These grafts were removed in the operating room and loaded into an injector. The next generation of eye bank-prepared graft was to preload the graft into an injector cartridge directly, ready to transfer into a syringe for implantation.
“A very useful adjunct in eye bank-prepared grafts is the addition of the ‘S’ mark, which tells you which is the right side up,” Kim said.
PDEK and partial DMEK grafts
The number of corneal transplantation procedures performed in the U.S. has remained stable in the past decade, but there has been a constantly growing number of endothelial procedures.
“More and more surgeons are moving toward this approach. DMEK in particular is continuously gaining ground: Numbers have been almost doubling each year since 2012. This trend shows that surgeons are becoming more and more comfortable with the procedure and want to offer the best quality of vision,” Kim said.
For those surgeons who feel more comfortable with DSAEK, there is the alternative to use thinner tissue and still achieve excellent results.
“Ultimately, we are able to provide a variety of keratoplasty procedures. Surgeons can decide on which one is the best depending on their skill set and patient population,” he said.
“I use DMEK with pre-stripped grafts and load them into the injector by myself,” OSN Cataract Surgery Board Member Sumit “Sam” Garg, MD, said.
“There is a learning curve. You have to understand the dynamics of the tissue and how to make it unfold. Once you get a handle on how to manipulate the graft within the eye, the procedure is straightforward. Advantages are the smaller incision, faster visual recovery and high postoperative satisfaction. I still use DSAEK in some high-risk eyes, but in general I switched all my straightforward cases to DMEK about 3 to 4 years ago,” he said.
For a short time in a few patients, Garg also used PDEK. The benefit of this technique is that the graft is slightly thicker, which makes it easier to manage than a DMEK graft and it can be harvested from younger donors. Drawbacks are the smaller diameter of the graft and the inability to re-evaluate endothelial cell viability after the tissue has been harvested.
“An air bubble is used to mechanically separate the tissue. Endothelial cell counters work from the surface in; therefore, you cannot image through an insufflated cornea that is opaque, making it difficult to assess endothelial cell structure after preparation,” Garg said.
However, the possibility of harvesting these grafts from a wider range of donors is a significant advantage in developing countries.
Other techniques that may be helpful when there is shortage of donor tissue are hemi-DMEK and quarter-DMEK.
“You double or quadruple the number of patients you can treat with one graft, which is advantageous in areas where there is limited access to eye banking. In the U.S., we have excess tissue; in other parts of the world, there is a shortage,” Garg said.
Endothelial cells, ROCK inhibitors
Some years ago, some authors reported cases in which spontaneous resolution of corneal edema occurred in patients with Fuchs’ dystrophy after removal of the Descemet’s membrane without an endothelial graft. It was hypothesized that the endothelium might have the ability to regenerate after removal of the central guttae by repopulating the area with healthy cells from the periphery. This opened up a new line of research, leading to two procedures. The first consists of the simple peeling of Descemet’s membrane (descemetorhexis without endothelial keratoplasty). The second, initiated by Shigeru Kinoshita, MD, PhD, involves localized removal of the diseased endothelium followed by injection of healthy cultured donor cells supplemented with a Rho kinase (ROCK) inhibitor or by multiple daily instillations of ROCK inhibitor eye drops to stimulate regeneration via the patient’s own cells.
Meanwhile, Holland and his group are preparing a U.S. study, replicating the work of Kinoshita, in which cell injection will be tested.
“Endothelial injection therapy is a tremendous breakthrough, not only because recovery is faster but also because one cornea can potentially supply up to 300 recipients. Our standard eye banking procedures in which one donor cornea can take care of one patient with corneal blindness works for the developed world but not for the developing world,” he said.
Bioengineered neo-corneas
Bioengineered neo-corneas, created using an expandable population of human donor-derived corneal endothelial cells could be another potential source of high-quality corneal tissue for transplantation.
Ophthalmologists at Wake Forest Baptist Medical Center have joined forces with the Institute for Regenerative Medicine and CorneaGen to engineer corneas from the replication of stem cells.
“We harvest endothelial stem cells from cadaver corneas, and using growth factors, we replicate them to form a single layer. We have been able to prove that they retain the characteristic pump function of the endothelium, which pumps the fluid from the cornea into the anterior chamber to keep the cornea relatively dehydrated. Placed on a scaffold, these cells are turned into a large sheet that can be used for transplantation. In this way, from a single donor we could potentially treat 70 to 100 patients,” OSN Refractive Surgery Board Member Keith A. Walter, MD, said.
The FDA is now awaiting results of more animal studies to confirm that cultured cells have the ability to regenerate the cornea after implantation. One of the concerns was that cells might grow uncontrollably and cause cancer, but scientists have shown that the cells exhibit contact inhibition and stop growing after reaching an endpoint.
“The whole process is extremely controlled. You can make sure that the cells have no viruses and are from a donor who has a good cell count and good health. Our current system of transplanting donor corneas still carries the risk of disease transmission from prion viruses and HIV,” Walter said.
Whereas using the patient’s own cells carries less risk for rejection, using donor cells has the advantage of not risking re-exposure to the disease.
After the conclusion of the preclinical phases within 6 months to 1 year, the group plans to present the data to the FDA to consider moving on to clinical trials.
“We are fortunate in the U.S. We have plenty of donors, but in other countries, there are issues with donation, mainly owing to cultural and religious taboos. In the U.S., we do 50,000 corneal transplantations a year, and we have 250,000 donors, fivefold more than we need. But in a country like China, there are approximately 5,000 donors and probably 300,000 people who need corneas. The old way of one-to-one donor-to-recipient is not the way to meet the challenge in the long term,” Walter said.
Epithelial stem cells
Research on stem cells is also progressing for dysfunctions that affect the anterior surface of the cornea after chemical or thermal injury and inflammatory diseases that result in conjunctival scarring and limbal failure such as Stevens-Johnson syndrome and mucous membrane pemphigoid. Hereditary diseases, such as congenital aniridia, constitute another big group.
“Standard corneal transplantation does not work for these patients because with limbal deficiency the donor epithelium ultimately fails. Patients with total limbal deficiency have a 0% chance of a successful penetrating or lamellar keratoplasty,” Holland said.
Currently, ocular surface stem cell transplantation (OSSTx) from a living related donor or deceased donor (keratolimbal allograft) is the best surgical option for severe ocular surface disease, but this requires oral immunosuppression, he said.
“We have found [immunosuppression] to be safe and well tolerated in the vast majority of our OSSTx patients. However, ophthalmologists are reluctant to use these medications, and therefore a limited number of corneal surgeons perform OSSTx. Ideally we need a source of ocular surface stem cells that are non-antigenic,” Holland said.
Artificial corneas
Innovative solutions have been proposed with artificial corneas. The KeraKlear artificial cornea (KeraMed) was first developed in 2009, has been approved in Europe and is under FDA trial in the U.S.
“The advantage is that it does not penetrate the eye, unlike the full-thickness Boston keratoprosthesis. It is implanted in a corneal pocket and potentially can be safer,” Holland said.
The CorNeat KPro artificial cornea (CorNeat Vision) is a PMMA lens that replaces the entire cornea and attaches to a nanofiber skirt that integrates into the conjunctival space. This technology may potentially reduce corneal melting that has been an issue with the Boston KPro.
But the most innovative idea in development is 3-D bioprinting of human corneas, according to Holland.
Starting from a digital design, the tissue is constructed layer by layer, using living cells mixed with biocompatible scaffold. Cells and scaffolds are combined and placed to grow in a culture incubator that re-creates the environment of a human body. The cells interconnect and are torn into living tissue, he said.
“By using this technology in the developing world, we would no longer need eye banks but could print the corneas locally to help patients with corneal disease,” Holland said. “In addition, there is the potential to 3-D print epithelial cells and limbal stem cells. This could eliminate the need for systemic immunosuppression and allow for all corneal specialists to perform OSSTx.”
Cost issues are a hurdle at present, but future evolutions of this technology may overcome this limitation. – by Michela Cimberle
Editor's note: This article has been updated to remove the North Carolina Eye Bank as an entity working with ophthalmologists at Wake Forest Baptist Medical Center. Ocular Surgery News regrets the error.
- References:
- Chan CC, et al. Cornea. 2016;doi:10.1097/ICO.0000000000000911.
- Cheung AY, et al. Cornea. 2018;doi:10.1097/ICO.0000000000001510.
- Choi JS, et al. Biomaterials. 2010;doi:10.1016/j.biomaterials.2010.05.020.
- Khor WB, et al. J Cataract Refract Surg. 2014;doi:10.1016/j.jcrs.2014.09.014.
- Kinoshita S, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1712770.
- Kinoshita S, et al. N Engl J Med. 2018;doi:10.1056/NEJMc1805808.
- Kurji KH, et al. Cornea. 2018;doi:10.1097/ICO.0000000000001697.
- Menzel-Severing J, et al. Br J Ophthalmol. 2017;doi:10.1136/bjophthalmol-2016-309550.
- Menzel-Severing J, et al. Curr Eye Res. 2018;doi:10.1080/02713683.2018.1501805.
- Movahedan A, et al. Am J Ophthalmol. 2017;doi:10.1016/j.ajo.2017.10.002.
- Okumura N, et al. Invest Ophthalmol Vis Sci. 2016;doi:10.1167/iovs.16-20123.
- Okumura N, et al. J Ophthalmol. 2017;doi:10.1155/2017/2646904.
- Okumura N, et al. PLoS One. 2018;doi:10.1371/journal.pone.0191306.
- Polisetti N, et al. Sci Rep. 2017;doi:10.1038/s41598-017-04916-x.
- For more information:
- Sumit “Sam” Garg, MD, can be reached at University of California, Irvine, 850 Health Sciences Road, Irvine, CA, 92697-4375; email: gargs@uci.edu.
- Edward J. Holland, MD, can be reached at the Cincinnati Eye Institute, 580 South Loop Road, Edgewood, KY 41017; email: eholland@holprovision.com.
- Terry Kim, MD, can be reached at Duke University Eye Center, Erwin Road, P.O. Box 3802, Durham, NC 27710-3802; email: terry.kim@duke.edu.
- Keith A. Walter, MD, can be reached at Wake Forest University Eye Center, 1 Medical Center Blvd., Winston-Salem, NC 27157; email: kwalter@wfubmc.edu.
Disclosures: Garg reports he is co-medical director of SightLife. Holland reports he is a consultant for CorneaGen and Precise Bio. Kim reports he is a consultant and shareholder of CorneaGen. Walter reports he is the medical director for CorneaGen and receives royalties for the EndoSerter.
Click here to read the 
, “Would you recommend Descemet’s stripping alone for Fuchs’ dystrophy?”