Disease-targeted surgery — decreased reliance on corneal donor tissue with more effective use of the donor tissues available and an integration of advanced technologies, such as femtosecond laser and OCT imaging — is the future of corneal transplantation. Additionally, the next decade should see another significant advance with injectable endothelial cells for the treatment of endothelial disease and integrated laser and imaging technologies, which will allow us to perform high-level precision keratoplasty.
Patients with endothelial disease or decompensation receive disease-targeted corneal transplantation, which has moved away from large incisions and thick donor tissue to thinner donor tissue and less invasive, smaller incisions. With this shift in tissue thickness, we have seen a corresponding shift in the improvement of final visual acuity and more rapid recovery of final visual outcomes.1 Whereas telling patients that it would take months for their final visual acuity to settle in, we are now telling patients that they can expect final results within weeks. From deep lamellar endothelial keratoplasty (DLEK) to Descemet’s automated endothelial keratoplasty (DSAEK), ultrathin DSAEK and finally Descemet’s membrane endothelial keratoplasty (DMEK), thinner transplanted tissue has resulted in visual outcome improvements and a decreased risk of rejection.2-4
With regard to keratoplasty, deep anterior lamellar keratoplasty (DALK) for anterior corneal disease, which allows for selective replacement of diseased corneal epithelium and stroma, is a disease-targeted advance. This technique allows for the replacement of the entire cornea except for Descemet’s membrane (DM) and the endothelium. The multiple benefits of DALK, including the safety of extraocular surgery, elimination of endothelial rejection, potential for shorter postoperative steroid use, and increased graft longevity, have made DALK the preferred option for corneal scars, stromal dystrophies, and keratoconus.5
Decreased Reliance on Donor Tissue
Descemet’s stripping only (DSO) or Descemet’s stripping without endothelial keratoplasty (DWEK) is a more recent therapeutic option for certain types of central endothelial disease, such as Fuchs endothelial corneal dystrophy, that bypasses the need for donor tissue altogether. In this type of surgery, the central 4 mm to 5 mm of diseased DM is removed via descemetorrhexis, and healthy peripheral endothelial cells are given time to migrate and reorganize centrally to clear the cornea. This procedure avoids completely the potential for rejection and the need for available endothelial keratoplasty donor tissue. Some studies have already pointed to its success in eyes that have central endothelial disease.6,7 The addition of a topical rho-kinase (ROCK) inhibitor may provide additional enhancement to the remaining endothelial cells for a more rapid corneal clearance.8 Investigations on this possibility are under way.
Cultured endothelial cells that can be injected into the anterior chamber and replenish or regenerate endothelial cell function constitute a novel and disruptive innovation for corneal transplantation. To be able to directly replace diseased and lost cells while maintaining a negligible risk of immunologic rejection will change the face of endothelial disease management. Innovation of this technology is being led by Dr. Shigeru Kinoshita in Japan, where initial human trials have shown highly promising results.9 Unpublished results from human trials in Japan are reporting 100% success in corneal clearance in eyes with bullous keratopathy from endothelial failure. The cornea community is anxiously awaiting the publication and detailing of this procedure and its long-term outcomes. ROCK inhibitors may also play a role in this technology by improving cell adhesion and phenotype differentiation.10,11
Integration of Advanced Technologies
Femtosecond laser technology for keratoplasty will continue to advance with innovations of faster, more precise lasers. Modifications in settings will allow for further corneal cut precision, customized trephinations, and lamellar smooth cuts through the posterior cornea. Initially pioneered for use in laser in-situ keratomileusis (LASIK) flap creation, the advent of the femtosecond laser has allowed for greater precision of wound architecture in both the host and donor tissue, allowing for earlier incision healing, improved approximation of tissue, and faster visual recovery with femtosecond laser-enabled keratoplasty (FLEK).12,13 Various configurations for keratoplasty incisions have been designed with the femtosecond laser, including, but not limited, to “top hat,” “mushroom,” and “zig-zag.” Evidence shows that these wound configurations allow for more surface area for tissue healing, contributing to decreased rates of wound leakage, the ability to remove sutures earlier, faster visual recovery, and improved postoperative astigmatism.14-16 FLEK has emerged as an alternative to conventional penetrating keratoplasty. The precision provided by the femtosecond laser allows for adequate scarring in as early as 4 months postoperatively, creating the opportunity for early suture removal and topical steroid tapering.17
Femtosecond big-bubble DALK combines the advantages of FLEK, including better donor-host fit, increased surface area apposition, and faster wound healing, as well as the advantages inherent to DALK in stromal and anterior corneal diseases.18,19 Recent advances in femtosecond laser cataract and corneal refractive surgery have made the technology common in many high-volume ophthalmic surgical centers. As advancing technology allows for smooth posterior lamellar cuts that are reproducible and precise, anterior lamellar keratoplasty for any stromal or anterior disease will become reproducible, and all current ambiguity regarding the successful creation of a big bubble will no longer be an issue.
Finally, the future of corneal transplantation will likely see an integration of intraoperative imaging into these technologies. The ability to use imaging modalities, such as optical coherence tomography (OCT), will greatly enhance the precision and accuracy of surgery with improved outcomes. Intraoperative OCT has already shown utility in endothelial keratoplasty and DALK procedures.20,21 Integration of OCT with the femtosecond laser (as seen in cataract laser platforms) will have the additional benefit of providing visualization of cut positions and altering of surgical planning, based on individual corneal shapes and anatomy. The future of corneal transplantation will see an integration of these technologies with expanded accessibility to all corneal surgeons.
On the Horizon
The future of corneal transplantation is exciting. Continued innovations in endothelial keratoplasty to decrease the need for corneal donor tissue and allow each corneal donor to provide therapy for many with cultured endothelial cell technology will help to address a global donor shortage and further move the needle of corneal therapeutics. Integrated laser and imaging advances will further our ability to customize and personalize anterior lamellar and full thickness transplant wound morphology and surgical options. Cataract and glaucoma surgeons have enjoyed technological advances that have changed the face of these fields. It is a long time coming to bring similar disruptive technology into the hands of corneal surgeons. CP
- Neff KD, Biber JM, Holland EJ. Comparison of central corneal graft thickness to visual acuity outcomes in endothelial keratoplasty. Cornea. 2011;30(4):388-391.
- Dickman MM, Kruit PJ, Remeijer L, et al. A randomized multicenter clinical trial of ultrathin Descemet stripping automated endothelial keratoplasty (DSAEK) versus DSAEK. Ophthalmology. 2016;123(11):2276-2284.
- Chamberlain W, Lin CC, Austin A, et al. Descemet endothelial thickness comparison trial: A randomized trial comparing ultrathin Descemet stripping automated endothelial keratoplasty with Descemet membrane endothelial keratoplasty. Ophthalmology. 2019;126(1):19-26.
- Anshu A, Price MO, Price FW Jr. Risk of corneal transplant rejection significantly reduced with Descemet’s membrane endothelial keratoplasty. Ophthalmology. 2012;119(3):536-540.
- Reinhart WJ, Musch DC, Jacobs DS, et al. Deep anterior lamellar keratoplasty as an alternative to penetrating keratoplasty a report by the american academy of ophthalmology. Ophthalmology. 2011;118(1):209-218.
- Garcerant D, Hirnschall N, Toalster N, Zhu M, Wen L, Moloney G. Descemet’s stripping without endothelial keratoplasty. Curr Opin Ophthalmol. 2019;30(4):275-285.
- Huang MJ, Kane S, Dhaliwal DK. Descemetorhexis without endothelial keratoplasty versus DMEK for treatment of Fuchs endothelial corneal dystrophy. Cornea. 2018;37(12):1479-1483.
- Macsai MS, Shiloach M. Use of topical rho kinase inhibitors in the treatment of Fuchs dystrophy after Descemet stripping only. Cornea. 2019;38(5):529-534.
- Kinoshita S, Koizumi N, Ueno M, et al. Injection of cultured cells with a ROCK inhibitor for bullous keratopathy. N Engl J Med. 2018;378(11):995-1003.
- Okumura N, Kinoshita S, Koizumi N. Application of rho kinase inhibitors for the treatment of corneal endothelial diseases. J Ophthalmol. 2017;2017:
- Okumura N, Koizumi N, Ueno M, et al. ROCK inhibitor converts corneal endothelial cells into a phenotype capable of regenerating in vivo endothelial tissue. Am J Pathol. 2012;181(1):268-277.
- Farid M, Steinert R, Garg S, Wade M. Femtosecond assisted penetrating keratoplasty. In: Cornea: Fundamentals, Diagnosis, and Management. Vol 2. 4th Edition. Krachmer JH, Mannis MJ, Holland EJ (editors). Philadelphia, PA: Elsevier Mosby; 2016.
- Farid M, Steinert RF, Gaster RN, et al. Comparison of penetrating keratoplasty performed with a femtosecond laser zig-zag incision versus conventional blade trephination. Ophthalmology. 2009;116(9):1638-1643.
- Price FW, Price MO. Femtosecond laser shaped penetrating keratoplasty: one-year results utilizing a top-hat configuration. Am J Ophthalmol. 2008;145(2):210-214.
- Cheng YY, Tahzib NG, van Rij G, et al. Femtosecond laser-assisted inverted mushroom keratoplasty. Cornea. 2008;27(6):679-685.
- Bahar I, Kaiserman I, Lange AP, et al. Femtosecond laser versus manual dissection for top-hat penetrating keratoplasty. Br J Ophthalmol. 2009;93(1):73-78.
- Shetty R, Kaweri L, Pahuja N, et al. Current review and a simplified “five-point management algorithm” for keratoconus. Indian J Ophthalmol. 2015;63(1):46-53.
- Buzzonetti L, Petrocelli G, Valente P. Femtosecond laser and big-bubble deep anterior lamellar keratoplasty: a new chance. J Ophthalmol. 2012;2012:264590.
- Shehadeh-Mashor R, Chan CC, Bahar I, et al. Comparison between femtosecond laser mushroom configuration and manual trephine straight-edge configuration deep anterior lamellar keratoplasty. The Br J Ophthalmol. 2014;98(1):35-39.
- Patel AS, Goshe JM, Srivastava SK, Ehlers JP. Intraoperative optical coherence tomography-assisted Descemet membrane endothelial keratoplasty in the DISCOVER study: First 100 cases. Am J Ophthalmol. 2020;210:167-173.
- De Benito-Llopis L, Mehta JS, Angunawela RI, Ang M, Tan DT. Intraoperative anterior segment optical coherence tomography: a novel assessment tool during deep anterior lamellar keratoplasty. Am J Ophthalmol. 2014;157(2):334-341.