REVIEW URRENT C OPINION

Descemet membrane endothelial transfer Fook Chang Lam a,b, Marieke Bruinsma a,c, and Gerrit R.J. Melles a,b,c

Purpose of review To elaborate on the recent concept of Descemet membrane endothelial transfer (DMET) and to explore the concepts that underpin its success through reviewing the key articles that have challenged our current understanding of corneal endothelial cell behavior. Recent findings DMET challenges the paradigm that complete graft–host apposition is required for successful corneal clearance in endothelial keratoplasty. It offers the promise of a simpler procedure to restore corneal clarity. Its success may lie in the ability of endothelial cells to migrate and proliferate. Endothelial host cells have been found in isolation and at disparate locations among donor cells within the corneal buttons of patients who have had a penetrating keratoplasty. New evidence for the continued slow proliferation of endothelial cells from the corneal periphery throughout life comes from the microanatomy of the peripheral cornea, and the demonstration of stem cell markers and markers of DNA synthesis in this area. Summary DMET offers us a tantalizing taste of a simpler way of treating corneal endothelial disease by harnessing the ability of corneal endothelial cells to migrate and proliferate. An understanding of these processes will be the key stepping stone to developing future treatments for corneal endothelial disease. Keywords Descemet membrane endothelial transfer, endothelial cell migration, endothelial cell proliferation, endothelial keratoplasty

INTRODUCTION For almost 100 years, full-thickness penetrating keratoplasty was the only definitive treatment for corneal endothelial disease. However, corneal surgery has, in the last decade, evolved and we have entered an era of selective lamellar corneal transplantation in which only the diseased portions of the cornea are replaced. The evolution of corneal surgery is such that we have moved on from penetrating keratoplasty through posterior lamellar keratoplasty (deep lamellar endothelial keratoplasty) and Descemet stripping endothelial keratoplasty (DSEK) to Descemet membrane endothelial keratoplasty (DMEK) [1]. DMEK provides superior visual acuity results, faster visual recovery rates, and lower complication rates. With the current DMEK techniques, it has been reported that in one series of 221 eyes, 98% of eyes reached a best corrected visual acuity (BCVA) of 20/40 or better, 79% achieved 20/25 or better, 46% reached 20/20, and 14% achieved 20/18 or better after 6 months [2 ]; whereas in another series of 81 eyes, 41% of the patients achieved a BCVA of 20/20 or better, 80% reached 20/25 or better, and 98% achieved 20/30 or better vision after 1 year [3]. &

Moving forward from DMEK, we published a paper in 2012 on a new surgical concept of Descemet membrane endothelial transfer (DMET), in which a ‘free-floating’ Descemet roll is implanted in the recipient chamber in order to induce corneal clearance [4 ]. In our current armamentarium of keratoplasty technique, where does DMET stand? &

WHY DO DESCEMET MEMBRANE ENDOTHELIAL TRANSFER? Despite the excellent visual outcomes, some surgeons hesitate in starting with DMEK because the procedure is deemed to be too difficult and to take too long to perform [5]. The difficult steps of DMEK a Netherlands Institute for Innovative Ocular Surgery, bMelles Cornea Clinic Rotterdam and cAmnitrans EyeBank Rotterdam, Rotterdam, The Netherlands

Correspondence to Gerrit R.J. Melles, MD, PhD, Netherlands Institute for Innovative Ocular Surgery, Rotterdam, the Netherlands. Tel: +31 10 297 4444; fax: +31 10 297 4440; e-mail: [email protected]; website: www.niios.com Curr Opin Ophthalmol 2014, 25:353–357 DOI:10.1097/ICU.0000000000000061

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KEY POINTS  DMEK has enabled the exact anatomical replacement of Descemet membrane and endothelium to allow the best visual acuity results and fastest visual recovery rates in the surgical treatment of corneal endothelial disease.  DMET provides a simpler and quicker surgical procedure that significantly reduces the surgical learning curve by removing some of the more technically challenging aspects of DMEK.  Cases of DMET and DMEK with significant endothelial graft detachments that have achieved corneal clearance challenge the paradigm in endothelial keratoplasty that complete graft-to-host cornea attachment is required for cornea clearance.  Both donor and remaining host endothelial cells may play a role in the restoration of corneal clarity after DMET.

are primarily to do with unfolding and attaching the graft [6]. These problems might be circumvented with the DMET technique. Here, surgery involves performing a 9-mm descemetorhexis and the subsequent injection of donor tissue, in the form of a Descemet roll, into the anterior chamber. As in DMET, it is assumed that the prerequisite for the restoration of corneal clarity is an area of contact between the donor Descemet roll and the host stroma [7], the upper edge of the graft is fixated within the corneal tunnel incision to secure a contact area between the graft and the host posterior stroma [4 ]. In contrast to DMEK, there is no need to unfold the Descemet roll or to completely attach the endothelial graft onto the recipient’s corneal surface. Therefore, DMET represents a tremendous simplification from DMEK because it eliminates the two most technically difficult parts of DMEK and also the need for an intraocular air bubble to induce and maintain graft attachment. Removing the need for an air bubble tamponade significantly shortens the duration of the surgical procedure and also removes the risk of pupillary block glaucoma because no air bubble is left in the anterior chamber. The simplification that DMET offers is certainly desirable, but how does DMET actually work? &

IS COMPLETE GRAFT-TO-HOST APPOSITION REQUIRED FOR A SUCCESSFUL OUTCOME AFTER ENDOTHELIAL KERATOPLASTY? The accepted paradigm for successful endothelial keratoplasty procedures has been that complete 354

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donor-to-host apposition of the transplanted endothelial graft to host cornea is required for the restoration of corneal clarity [8], so that graft detachment was considered indicative of a poor clinical outcome. However, corneal clearance has been demonstrated despite subtotal graft detachment in eyes that have undergone DSEK [9] and DMEK [10]. These cases challenged the concept that the complete anatomical attachment of a graft with an intact corneal endothelial layer was required for the restoration for corneal clarity. Furthermore, this demonstrated that it is possible to re-establish corneal clearance despite only a very small area of donorto-host apposition. This leads to the question of whether donor-corneal host attachment is required at all to induce corneal clearance after endothelial keratoplasty.

IS DONOR-CORNEAL HOST ATTACHMENT REQUIRED AT ALL? In an evaluation of 150 consecutive eyes with DMEK, in which 16 eyes showed a partially detached DMEK graft (less than one-third of the graft surface area) and 7 eyes showed a large detachment (greater than one-third), corneas with partial (less than onethird) or large (greater than one-third) detachments still cleared successfully, but eyes with a ‘free-floating Descemet roll’, that is without contact between the donor graft and the host corneal stroma, failed to clear [7]. This demonstrates that the mere presence of endothelial tissue within the anterior chamber alone might be insufficient to drive recovery and the restoration of corneal clarity. Therefore, some direct physical contact between donor tissue and host cornea may be required as well for corneal clearance.

WHAT IS THE MECHANISM OF CORNEAL CLEARANCE AFTER DESCEMET MEMBRANE ENDOTHELIAL TRANSFER? How does the cornea clear after DMET when the graft is only in contact with a small area of the host stroma? In DMEK corneas that have regained clarity despite significant graft detachment [9,10], it was suggested that endothelial cell migration and proliferation are possible mechanisms by which cornea clearance might be achieved. However, endothelial cell proliferation in human corneas is thought to be rare with the cornea compensating for endothelial cell loss by the enlargement and spreading of remaining adjacent live endothelial cells. The potential for human corneal endothelial cells to migrate in normal human eyes has been suggested by the spontaneous resolution of corneal Volume 25  Number 4  July 2014

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Descemet membrane endothelial transfer Lam et al.

edema following large persistent Descemet membrane detachments following cataract surgery [11]. In addition, histological assessment of a DSEK graft confirmed the presence of endothelial cells that have migrated to cover the bare stromal margin of the DSEK button with the formation of new Descemet membrane [12]. Furthermore, Jacobi et al. [13] demonstrated, using in-vivo confocal laser scanning microscopy in individual patients following DMEK, that areas of denuded corneal stroma in the recipients were covered with a complete endothelial layer after 1 year. The morphologic phenotype, pattern, and density of the endothelium resembled the central endothelium of the graft, suggesting that the source of the endothelium was from the graft. Additional evidence for the migration of human corneal endothelial cells comes from an evaluation of corneal buttons removed from patients who had undergone penetrating keratoplasty. Lagali et al. [14] revealed that the recipient endothelium can, to variable extents, populate the donor button. In some cases, individual cells from the peripheral recipient endothelium appeared to have migrated far into the graft at disparate locations.

important role of donor endothelial tissue for reliably restoring corneal clarity. Be that as it may, it does appear that the recipient corneal endothelium plays a role in the restoration of corneal clarity with DMET. In a series of 12 eyes undergoing DMET, all 7 eyes operated on for Fuchs endothelial dystrophy showed progressive corneal clearance, whereas no improvement was found for the 5 eyes operated on for aphakic and pseudophakic bullous keratopathy [17 ]. The apparent reason for this difference in efficacy may lie in the fact that with bullous keratopathy there may be a significant depletion of host corneal endothelial cells, whereas in Fuchs endothelial dystrophy, the endothelium of the peripheral cornea may be relatively spared. This is especially as Fuchs endothelial dystrophy probably represents a phenotypic continuum with a significant genetic overlap, and in some situations there could be a mosaic of nonaffected and affected cells [18]. Therefore, it appears that both donor and remaining host endothelial cells play a role in the restoration of corneal clarity after DMET.

DONOR VERSUS HOST ENDOTHELIUM: WHAT DRIVES THE RECOVERY?

Although endothelial cell migration appears to play a crucial role in the recovery of corneal clarity for patients who have undergone DMET, it is not entirely clear to what extent endothelial cell proliferation may also contribute to the whole process of corneal deturgescence and clearance in these cases. Human endothelial cells have mitotic ability in vitro, but they are arrested in the G1-phase in vivo [19]. Mitotic inhibition is brought about by the presence of transforming growth factor b in aqueous humor, lack of effective growth factor stimulation, and by cell–cell contact inhibition [20]. Therefore, corneal endothelial cells usually have a limited capacity for wound healing in vivo, and compensatory endothelial cell enlargement and sliding of remaining adjacent endothelial cells are the mechanisms by which the defects left by lost endothelial cells are usually covered. However, with reports of spontaneous recovery following inadvertent or intentional Descemet stripping alone, the situation may be different in cases of extensive corneal endothelial wounding in some individuals. The question then would be whether corneal endothelial cell proliferation might take place in the cornea periphery of the host or in the donor endothelial tissue.

Although such work demonstrates that endothelial cell migration can move from the direction of the recipient into donor tissue and vice versa, it is uncertain whether it is the graft or the host peripheral endothelium that is the more important source of endothelial cells in re-establishing corneal deturgescence and clarity after DMET. This uncertainty arises because the capacity of the recipient’s own corneal endothelium for migrating and proliferating might be more limited in cases of endothelial disease. Corneal clearance with endothelial cell repopulation of the posterior stroma in a patient with endothelial disease has been reported following Descemet stripping without endothelial replacement in a patient with posterior polymorphous membrane dystrophy (PPMD) [15]. In this case, the authors speculated that the patient’s underlying condition of PPMD and young age may have facilitated endothelial cell migration. The results with Descemet stripping alone in Fuchs endothelial dystrophy has been shown to be disappointing. Only three out of eight patients with Fuchs endothelial dystrophy undergoing Descemet stripping (with simultaneous phacoemulsification with intraocular lens implantation) showed some corneal clearing and only one out of eight maintained a clear cornea at 18 months postoperatively [16]. Nevertheless, such dismal results with Descemet stripping alone in Fuchs endothelial dystrophy point to the

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DOES ENDOTHELIAL CELL PROLIFERATION PLAY A ROLE?

WHERE MIGHT ENDOTHELIAL CELL PROLIFERATION TAKE PLACE? It has been suggested that stem-like corneal endothelial cells may be sequestered in a niche at the junctional region, where the corneal endothelial

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cells and the trabecular meshwork come together [21,22 ]. Following mechanical wounding, human corneal endothelial cells in this peripheral region have demonstrated positive telomerase activity (a stem-like cell associated marker) and stained positively with bromodeoxyuridine (indicating new DNA synthesis) [21]. Further evidence of human corneal endothelial cell proliferation existing in the extreme periphery of human corneas in vivo comes from the work looking at the microanatomy of the corneal endothelial periphery. He et al. [22 ] demonstrated the organization of endothelial cells into small clusters with two to three cell layers around Hassall-Henle bodies in the extreme periphery and the organization of peripheral corneal endothelial cells in radial rows in the corneal periphery. The endothelial cells in the extreme periphery exhibited lesser differentiation, preferentially expressed stem cell markers and rarely also expressed the proliferation marker Ki67. The authors suggested that this anatomic organization suggested a continuous slow centripetal migration of endothelial cells from specific niches throughout life. Such work and the fact that the cornea can clear after Descemet stripping alone despite endothelial disease [15,16] does raise the question of whether endothelial cell proliferation from the corneal periphery may contribute to corneal recovery in DMET, and if so to what extent. Following on from this, a further question is whether the corneal endothelial cells in patients with corneal endothelial disorders, such as Fuchs endothelial dystrophy, still have the capacity to proliferate. &&

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CAN DISEASED ENDOTHELIAL CELLS STILL PROLIFERATE? &&

Zaniolo et al. [23 ] have demonstrated that it is possible to isolate and culture endothelial cells from the central Descemet membranes of patients suffering from Fuchs endothelial dystrophy. This observation that human corneal endothelial cells can be harvested and cultured even from areas where the dystrophy is more advanced suggests that perhaps in some situations, there may be some contribution from the host peripheral corneal endothelium through endothelial cell proliferation. If this is true, it may partially explain why patients with Fuchs endothelial dystrophy do better with DMET compared with those with pseudophakic and aphakic bullous keratopathy [17 ]. It also opens up new possibilities for future therapies which could be aimed at stimulating a patient’s remaining endothelial cells to proliferate.

corneal endothelial cell sheets to treat endothelial disease. Koizumi et al. [24] developed a model in which cultivated corneal endothelial cells on type 1 collagen sheets were transplanted into cynomolgus monkeys. Although in all four cases the cultivated monkey corneal endothelial cell sheets detached by 14 days, corneal clarity was maintained at least up to 6 months. At 6 months after transplantation, the posterior corneal surface was covered by a confluent layer of polygonal cells, and a new basement membrane and endothelial cell densities of 2475 and 1992 cells/mm2 were reported. The group postulated that the procedure’s success was because of cultivated monkey corneal endothelial cells migrating onto the host Descemet membrane and proliferating in vivo after retaining its proliferative ability despite being returned to the in-vivo environment. However, whether such success can be translated to humans remains to be seen. Moving even further forward, some researchers are currently working on stimulating the proliferation of host corneal endothelial cells as a means of treating endothelial disease [25–27,28 ]. &

CONCLUSION In the present state of affairs, corneal endothelial diseases such as Fuchs endothelial dystrophy, pseudophakic bullous keratopathy, congenital hereditary endothelial dystrophy, iridocorneal endothelial syndrome, and posterior polymorphous dystrophy still require endothelial keratoplasty for the restoration of corneal clarity. In these cases, DMEK still provides excellent and rapid visual recovery, whereas DMET offers us a technically more simple procedure that has also rendered us a deeper understanding of the processes involved in endothelial cell wound healing. Acknowledgements Financial disclosure: No author has a financial or proprietary interest in any material or method mentioned. Conflicts of interest G.R.J.M. is a consultant for D.O.R.C. International/ Dutch Ophthalmic USA. The remaining authors have no conflicts of interest to declare.

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FUTURE PERSPECTIVES Taking DMET a step further, it may be possible to apply the DMET technique to the use of cultivated 356

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REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Dapena I, Ham L, Melles GR. Endothelial keratoplasty: DSEK/DSAEK or DMEK – the thinner the better? Curr Opin Ophthalmol 2009; 20:299– 307.

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Descemet membrane endothelial transfer Lam et al. 2. Van Dijk K, Ham L, Tse WH, et al. Near complete visual recovery and refractive & stability in modern corneal transplantation: Descemet membrane endothelial keratoplasty (DMEK). Cont Lens Anterior Eye 2013; 36:13–21. This article describes the clinical outcome after Descemet membrane endothelial keratoplasty in a series of 300 eyes. 3. Guerra FP, Anshu A, Price MO, et al. Descemet’s membrane endothelial keratoplasty: prospective study of 1-year visual outcomes, graft survival, and endothelial cell loss. Ophthalmology 2011; 118:2368–2373. 4. Dirisamer M, Ham L, Dapena I, et al. Descemet membrane endothelial & transfer: ‘Free-floating’ donor Descemet implantation as a potential alternative to ‘keratoplasty’. Cornea 2012; 31:194–197. This article describes a case of corneal clearance despite subtotal detachment of the DMEK graft. 5. Terry MA. Endothelial keratoplasty: why aren’t we all doing Descemet membrane endothelial keratoplasty? Cornea 2012; 31:469–471. 6. Cursiefen C. Descemet membrane endothelial keratoplasty: the taming of the shrew. JAMA Ophthalmol 2013; 131:88–89. 7. Dirisamer M, Dapena I, Ham L, et al. Patterns of corneal endothelialization and corneal clearance after Descemet membrane endothelial keratoplasty for Fuchs endothelial dystrophy. Am J Ophthalmol 2011; 152:543– 555. 8. Romaniv N, Price PO, Price FW, et al. Donor Descemet membrane detachment after endothelial keratoplasty. Cornea 2006; 25:943–947. 9. Zafrakis P, Kymionis GD, Grentzelos MA, Livir-Rallatos G. Corneal graft detachment without corneal edema after Descemet stripping automated endothelial keratoplasty. Cornea 2010; 29:456–458. 10. Balachandran C, Ham L, Verschoor CA, et al. Spontaneous corneal clearance despite graft detachment in Descemet membrane endothelial keratoplasty (DMEK). Am J Ophthalmol 2009; 148:227–234. 11. Watson SL, Abiad G, Coroneo MT. Spontaneous resolution of corneal oedema following Descemet’s detachment. Clin Exp Ophthalmol 2006; 34:797–799. 12. Stewart RMK, Hiscott PS, Kaye SB. Endothelial migration and new Descemet membrane after endothelial keratoplasty. Am J Ophthalmol 2010; 149:683– 684. 13. Jacobi C, Zhivov A, Korbmacher J, et al. Evidence of endothelial cell migration after Descemet membrane endothelial keratoplasty. Am J Ophthalmol 2011; 152:537–542. 14. Lagali N, Stenevi U, Claesson M, et al. Donor and recipient endothelial cell population of the transplanted human cornea: a two-dimensional imaging study. Invest Ophthalmol Vis Sci 2010; 51:1898–1904. 15. Shah RD, Randleman JB, Grossniklaus HE. Spontaneous corneal clearing after Descemet’s stripping without endothelial replacement. Ophthalmology 2012; 119:256–260. 16. Bleyen I, Saelens IE, van Dooren BT, et al. Spontaneous corneal clearing after Descemet’s stripping. Ophthalmology 2013; 120:215.

17. Dirisamer M, Yeh RY, van Dijk K, et al. Recipient endothelium may relate to corneal clearance in Descemet membrane endothelial transfer. Am J Ophthalmol 2012; 154:290–296. This article describes the importance of recipient endothelium in corneal clearance after DMET by comparing the outcomes of DMET in eyes with Fuchs endothelial dystrophy against eyes with bullous keratopathy. 18. Bruinsma M, Tong CM, Melles GRJ. What does the future hold for the treatment of Fuchs endothelial dystrophy; will ‘keratoplasty’ still be a valid procedure? Eye 2013; 27:1115–1122. 19. Joyce NC, Meklir B, Joyce SJ, et al. Cell cycle protein expression and proliferative status in human corneal cells. Invest Ophthalmol Vis Sci 1996; 37:645–655. 20. Joyce NC. Proliferative capacity of corneal endothelial cells. Exp Eye Res 2012; 95:16–23. 21. Whikehart DR, Parikh CH, Vaughn AV, et al. Evidence suggesting the existence of stem cells for the human corneal endothelium. Mol Vis 2005; 11:816–824. 22. He Z, Campolmi N, Gain P, et al. Revisited microanatomy of the corneal && endothelial periphery: new evidence for continuous centripetal migration of endothelial cells in humans. Stem Cells 2012; 30:2523–2534. This article describes a novel anatomic organization in the periphery of the human corneal endothelium, suggesting a continuous slow centripetal migration throughout the life of endothelial cells from specific niches. 23. Zaniolo K, Bostan C, Rochette Drouin O, et al. Culture of human corneal && endothelial cells isolated from corneas with Fuchs endothelial corneal dystrophy. Exp Eye Res 2012; 94:22–31. This article describes that central Descemet membranes of patients suffering from FED possess proliferative endothelial cells that can be isolated and cultured without viral transduction. 24. Koizumi N, Sakamoto Y, Okumura N, et al. Cultivated corneal endothelial cell sheet transplantation in a primate model. Invest Ophthalmol Vis Sci 2007; 48:4519–4526. 25. Koizumi N, Okumura N, Ueno M, et al. Rho-associated kinase inhibitor eye drop treatment as a possible medical treatment for Fuchs corneal dystrophy. Cornea 2013; 32:1167–1170. 26. Okumura N, Koizumi N, Ueno M, et al. Enhancement of corneal endothelium wound healing by Rho-associated kinase (ROCK) inhibitor eye drops. Br J Ophthalmol 2011; 95:1006–1009. 27. 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; 181:268–277. 28. Okumura N, Koizumi N, Kay EP, et al. The ROCK inhibitor eye drop accel& erates corneal endothelium wound healing. Invest Ophthalmol Vis Sci 2013; 54:2493–2502. This article describes that ROCK inhibitor Y-27632 eye drops promote corneal endothelial wound healing in a primate animal model and suggests that Y-27632 eye drops improved the corneal edema of human patients with central edema because of corneal endothelial dysfunction. &&

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Descemet membrane endothelial transfer.

To elaborate on the recent concept of Descemet membrane endothelial transfer (DMET) and to explore the concepts that underpin its success through revi...
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