5 Corneal Endothelial Reconstruction: Current and Future Approaches
Summary
Visual loss from corneal endothelial failure is a leading indication for corneal transplantation. The concept of selective replacement of damaged or lost endothelial cells using lamellar keratoplasty techniques has revolutionized the treatment of corneal endothelial failure over the past two decades. Current endothelial keratoplasty techniques, Descemet’s stripping endothelial keratoplasty (DSEK), Descemet’s stripping automated endothelial keratoplasty (DSAEK), and Descemet’s membrane endothelial keratoplasty (DMEK), are associated with improved visual outcomes, lower risks of graft rejection, and superior graft survival rates compared to full-thickness penetrating keratoplasty (PK) procedures. With continual refinements and advancements in such endothelial keratoplasty techniques, these procedures are getting more effective in reversing corneal blindness caused by corneal endothelial failure. However, being donor-dependent, access to corneal transplantation is limited by a global shortage of available donor tissue. The difference between donor cornea availability and demand for corneal transplants has, therefore, driven a search for alternative treatment modalities for corneal endothelial replacement. Research into such alternative therapies currently focuses on two main areas: regenerative medicine and cell-based approaches. This chapter aims to provide an overview of current transplantation techniques used to treat endothelial failure and the limitations of each of these procedures. Novel therapies that are on the horizon for the treatment of corneal endothelial failure will also be introduced.
5.1 Introduction
Visual loss from corneal endothelial failure is a leading indication for corneal transplantation. A shift towards lamellar keratoplasty techniques for the treatment of corneal blindness have resulted in faster visual rehabilitation and lower rates of graft complications. This chapter describes the surgical techniques currently used to treat endothelial failure, the limitations of such procedures, and potential future approaches to replace the diseased corneal endothelium.
5.2 The Corneal Endothelium in Health
The corneal endothelium is the innermost single-cell layer of the cornea. It plays an important role in the dynamic maintenance of corneal hydration. Corneal endothelial cells are connected by intercellular junctions, which are tight but leaky, allowing passive diffusion of fluid from the anterior chamber across the corneal endothelium into the corneal stroma. 1 Conversely, active ionic pumps, such as the Na+/K+ adenosinetriphosphatase transporter, move fluid against an osmotic gradient from the corneal stroma back into the anterior chamber. 2 , 3 , 4 Such “pump-leak” mechanisms maintain corneal aqueous content at an ideal level—78% water. This supports optimal interlamellar spacing of collagen fibrils within the corneal stroma and corneal transparency. 5 , 6
At birth, the average human corneal endothelial cell density is approximately 6,000 cells/mm 2 . 7 This falls to about 3,500 cells/mm 2 by 5 years of age, as a result of physiological cell loss and concurrent corneal growth. Throughout life, there is a gradual decline of endothelial cell density of approximately 0.6% per year. This natural loss in endothelial cells with age does not usually result in any clinically significant impairment in corneal structure and function.
5.3 The Corneal Endothelium in Disease
Diseases of the corneal endothelium, such as Fuchs’ endothelial corneal dystrophy (FECD) or ocular insults including intraocular surgeries, anterior segment laser therapies, ocular trauma, or inflammation, can result in an accelerated loss of corneal endothelial cells. When the corneal endothelial cell density falls below a certain level, the ability of the corneal endothelium to regulate corneal hydration becomes impaired. 8 , 9 , 10 In corneal endothelial failure, the cornea becomes edematous, resulting in loss of corneal transparency and eventually blindness.
Human corneal endothelial cells are thought not to regenerate in vivo. 11 , 12 At approximately 6 weeks of human gestation, corneal endothelial cells are arrested in the quiescent, nonproliferative G1 phase of the cell cycle. 13 , 14 Studies have shown that the lack of ability for human corneal endothelial cells to proliferate in vivo is attributed to a combination of factors such as cell–cell contact-dependent inhibition, 15 , 16 a lack of effective growth factor stimulation, 16 , 17 and the presence of rich mitotic inhibitors such as transforming growth factor (TGF-β) isoforms present in the aqueous humour. 15 , 16 , 17 , 18 , 19 Both TGF-β1 and -β2 isoforms have been shown to block endothelial cell proliferation by suppressing an entry into the S phase of the cell cycle, perhaps via an upregulation of the G1-phase inhibitor, p27(Kip1). 20 , 21
As corneal endothelial cells are unable to spontaneously regenerate in vivo when the corneal endothelial cell density falls to a pathological level (typically <500–600 cells/mm 2 ), the restoration of physiological corneal endothelial function depends on: (1) replenishment with an exogenous source of cells (corneal transplantation or cell-based therapies); (2) repair of damaged cells (regenerative medicine), or (3) redistribution of remaining cells to replace lost cells (regenerative medicine).
5.4 Corneal Endothelial Replacement: Current Approaches
In current clinical practice, corneal transplantation is the predominant treatment for corneal blindness caused by endothelial dysfunction. For more than half a century, penetrating keratoplasty (PK) has been the main procedure for the treatment of most causes of corneal blindness. This is a full-thickness transplant; all layers of the cornea are replaced with a donor PK graft fixed with sutures.
Over the past 15 to 20 years, there has been a fundamental shift in the treatment of corneal diseases towards replacing only diseased parts of the cornea. 22 , 23 Indeed, the concept of selective replacement of damaged endothelial cells has revolutionized the treatment of corneal endothelial failure. 23 In the late 1990s, Melles et al first described an intrastromal approach for posterior lamellar keratoplasty. 24 This selectively replaced only diseased corneal endothelium and avoided full-thickness surgery. Subsequent modifications of this technique have since led to more advanced endothelial keratoplasty techniques with improved visual outcomes and graft survival rates. These procedures have now replaced PK as mainstay techniques for treating endothelial dysfunction. 25 In current clinical practice worldwide, there are two leading techniques for endothelial keratoplasty: (1) Descemet’s stripping automated endothelial keratoplasty (DSAEK) or Descemet’s stripping endothelial keratoplasty (DSEK), depending on how the donor graft is cut, and (2) Descemet’s membrane endothelial keratoplasty (DMEK). 22 , 23 , 26
In this chapter, we aim to provide an overview of DSAEK/DSEK and DMEK. We will also introduce novel therapies that are on the horizon for the treatment of corneal endothelial failure.
5.4.1 Descemet’s Stripping Automated Endothelial Keratoplasty or Descemet’s Stripping Endothelial Keratoplasty
In DSAEK/DSEK, transplanted donor endothelial grafts consist of donor endothelium, Descemet’s membrane (DM), and some posterior stroma. In DSAEK, an automated microkeratome is used to cut donor grafts. 27 In institutions where automated microkeratomes are not available, a lamellar dissection technique can be used to cut the endothelial graft. 28 This manual technique is termed DSEK.
In DSAEK/DSEK, the central DM is stripped from the recipient’s stroma with its diseased endothelium (descemetorhexis). Through a small corneal or scleral incision, the cut donor endothelial graft is transferred into the patient’s anterior chamber. It is then made to attach to the posterior cornea without sutures, by the use of air or gas tamponade (▶Fig. 5.1).
DSAEK/DSEK procedures have several advantages over PK. Unlike PK, they are minimally invasive, avoiding full-thickness central corneal trephination and intraoperative “open sky” situations, thereby reducing the risk of sight-threatening complications like expulsive hemorrhage. DSAEK/DSEK also offer better mechanical integrity and globe strength. In the event of ocular trauma, the risk of sight-threatening open-globe injuries is higher in eyes that had undergone PK compared to eyes that had undergone DSAEK/DSEK because PK is associated with inherent weakness at the graft–host junction. Furthermore, DSAEK/DSEK are less likely to induce postoperative corneal astigmatism as central corneal sutures are not needed. This allows faster visual rehabilitation. 29 Corneal suture-related problems and ocular surface disorders, seen commonly following PK, occur less frequently after DSAEK/DSEK. As less donor tissue is transplanted in DSAEK/DSEK than in PK, studies have also shown that DSAEK/DSEK procedures are associated with a lower risk of rejection. 30 Lastly, DSAEK/DSEK allow more accurate intraocular lens (IOL) power calculations when combined with cataract extraction, as they do not change the corneal profile as much as PK.
Given the advantages over PK, DSAEK/DSEK have overtaken PK as primary procedures for the treatment of corneal endothelial failure in many centers worldwide. With the increasing popularity of DSAEK/DSEK among corneal surgeons, research has focused on methods to improve the postoperative outcomes of these surgical techniques. One example of a significant advance is in the techniques used to insert donor endothelial grafts. When DSAEK/DSEK were first performed, donor endothelial graft insertion was carried out using a “folding” technique. 25 The donor tissue was folded into a 60/40 “taco” shape and inserted into the anterior chamber using forceps. The donor tissue was then unfolded in the eye. The problem with the folding technique is that it was associated with significant endothelial cell loss. Specular microscopy and scanning electron microscopy studies have reported up to 30 to 40% endothelial cell loss with the folding technique. 31
Newer methods of graft insertion that are less traumatic to the endothelial cells have since been introduced. Some examples are the use of modified lens cartridges or an IOL sheet glide to push or pull the endothelial graft into the anterior chamber. 32 Furthermore, customized endothelial graft insertion devices have also been developed. Examples of these devices include the Busin glide (Asico, USA), 33 the EndoGlide (Network Medical Products, UK), 34 the Endosaver (Ocular Systems Inc, USA), among various others. These newer methods and devices maintain graft orientation stromal side up during graft insertion and are less traumatic to the endothelium as they minimize the need for intraocular manipulation when unfolding the graft. They also prevent endothelial cell to endothelial cell touch during donor insertion. The risk of cell loss is thus reduced.
▶Fig. 5.2 shows the technique of graft loading and insertion using the EndoGlide. The harvested graft is loaded and made to scroll in the EndoGlide with minimal contact and trauma to donor endothelial cells. The insertion technique using the EndoGlide maintains anterior chamber stability and orientation of the donor endothelial graft, avoiding excessive intraocular manipulation and thus preventing endothelial cell loss.
Another key development in DSAEK surgery relates to the thickness of the transplanted endothelial graft. The transplantation of ultrathin DSAEK grafts, defined as grafts of less than 100-µm thickness, has been reported to have improved visual outcomes compared to the transplantation of thicker grafts. 35 , 36 To consistently create thin endothelial grafts, various strategies have been proposed. One of these strategies includes a “double-pass technique.” 37 , 38 In this technique, an initial debulking cut is performed with a 300-µm head microkeratome; this is followed by a second refinement cut, depending on the residual corneal thickness after the first cut. Another strategy described to create thin endothelial grafts involves the preconditioning of donor tissue by stromal dehydration. 39 By using an airflow dehydration device to control the thickness of donor corneas before the microkeratome dissection, the predictability of achieving ultrathin DSAEK grafts is increased. Furthermore, the use of a femtosecond laser in combination with a microkeratome to create thin endothelial grafts has also been proposed. 40 More recently, studies have reported that the transplantation of nanothin DSAEK grafts (defined as grafts 50 µm) can achieve even better visual outcomes compared to ultrathin grafts. 41
Nevertheless, despite significant improvements in surgical techniques and good visual outcomes, DSAEK/DSEK have their limitations. The transplantation of a layer of posterior corneal stroma in DSAEK/DSEK grafts can induce unwanted hyperopic shifts. Suboptimal visual recovery may also result from optical quality degradation at the graft–host lamellar interface. 42 , 43
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