Current concepts and recent trends in endothelial keratoplasty

Abstract

Endothelial keratoplasty (EK) is defined as an umbrella term comprising methods for selective surgical replacement of corneal endothelium and adjacent corneal tissue, which retains healthy portions of a patient's cornea while replacing diseased innermost corneal layer(s) with healthy donor tissue, to achieve corneal dehydration and transparency before the onset of irreversible stromal edema and permanent loss of corneal clarity. Recently, the pathophysiology of corneal decompensation is increasingly being researched upon. Consequent improvement in pharmacotherapy is progressively leading to reduction in the indications of EK. In addition, EK techniques have progressed towards using thinner tissue, optimizing visual outcomes. Improvements have enabled better donor tissue formulation, usage, and attachment, and surgical modifications have enhanced the tissue utilization in difficult clinical scenarios lowering failure and rejection. However, challenges are encountered in various complex clinical scenarios including eyes with prior intraocular surgery, complex anterior chamber anatomy, glaucoma, ocular surface disease etc. These complexities demand tailored surgical strategies, including modifications in graft handling, instrumentation, and postoperative management to ensure success. Attention to these details and addressing patient-specific factors can help improve outcomes in these difficult cases. The choice of procedure depends on multiple factors, including the surgeon's experience, patient's ocular anatomy, and the specific clinical scenario. This review article encompasses the recent developments in this field presenting a comprehensive picture of our modern understanding of the indications, contraindications, surgical techniques, clinical situations, community aspects and future directions pertaining to EK.

Key Words: Cell-and tissue-based Therapy; Corneal transplantation; Descemet stripping endothelial keratoplasty; Immunosuppression therapy; Refractive surgical procedures

Core Tip: Endothelial keratoplasty (EK) refers to selective surgical replacement of corneal endothelium and adjacent corneal tissue, which retains healthy portions of a patient's cornea while replacing diseased innermost corneal layer(s) with healthy donor tissue. EK techniques have progressed towards using thinner tissue, optimizing visual outcomes. Increasingly complex clinical scenarios demand tailored surgical strategies, including modifications in graft handling, instrumentation, and postoperative management to ensure success. In addition, addressing patient-specific factors can help improve outcomes in these difficult cases. The choice of procedure depends on multiple factors, including the surgeon's experience, patient's ocular anatomy, and the specific clinical scenario.

INTRODUCTION

Endothelial keratoplasty (EK) is defined as an umbrella term comprising methods for selective surgical replacement of corneal endothelium and adjacent corneal tissue, which retains healthy portions of a patient's cornea while replacing diseased innermost corneal layer(s) with healthy donor tissue[1].

All kinds of posterior corneal lamellar transplantation procedures include the corneal endothelium, and are thus classified as EK. Briefly, EK encompasses dissection of the posterior lamellar corneal tissue (lenticule) of the recipient cornea by a maneuver called Descemetorhexis, its displacement into the anterior chamber (AC) and removal through an incision in the peripheral cornea. A donor posterior lenticule is then inserted into the AC and apposed to the recipient bed using a large air or gas bubble filling the AC. The surgery is often sutureless and can be performed through sclerocorneal tunnel or clear corneal incisions, with additional limbal paracenteses and an inferior (Ando’s) peripheral iridotomy that reduces the chances of pupillary block[2].

The evolution and ongoing refinement of EK techniques have solidified its crucial role in modern corneal surgery[3]. Many published review articles cover the understanding of the pathophysiology of corneal endothelial dysfunction and classically described techniques of EK. However, key gaps remain in literature comparing and contrasting classical and newer techniques, dwelling on the management of challenges encountered in various complex clinical scenarios (including eyes with prior intraocular surgery, complex AC anatomy, glaucoma, ocular surface disease etc.), tailored surgical strategies including modifications in graft handling, modern instrumentation, postoperative management, patient specific factors, costs, regulatory nuances and ethical concerns, that are inadequately addressed in previous reviews[1,4-7]. This review is an attempt to discuss all these aspects to present an inclusive iterative overview of this essential surgical technique, thereby providing valuable insights for clinicians to choose the best practices for the benefit of patients.

SEARCH METHODOLOGY

A comprehensive literature search was performed in PubMed, Scopus and Google Scholar, comprising of the search terms as follows: Cornea, endothelium, endothelial, dysfunction, dystrophy, degeneration, transplantation, keratoplasty, lamellar, pre-cut, Descemet’s membrane (DM), Descemet’s stripping, FS laser, pre-Descemet Dua’s layer, descemetorhexis, donor, recipient, host, graft, rejection, failure, edema, detachment and corneal scar.

The search strategy initially included studies published after 2008 to capture recent advancements in surgical techniques, instruments, and patient outcomes in EK procedures. This timeframe was chosen to reflect the rapid evolution of these procedures and the incorporation of advanced technology in clinical practice. However, the contributions of earlier seminal research that established the foundation for current practices cannot be ignored. To provide a balanced perspective, the authors additionally reviewed key pre-2008 studies to contextualize the historical development and to complement the review of contemporary advancements. Emphasis was provided to the use of reference citation analysis for highlighting the most impactful articles pertaining to the subject matter, which were reviewed.

Six independent reviewers evaluated the abstracts and full texts of 2644 articles for significance and utility. After removing duplicates, articles not pertaining to corneal endothelial lamellar keratoplasty in humans, purely in-vitro and animal studies, and foreign language articles without available English language translations were excluded. Finally, 166 articles were considered for the review.

UNDERSTANDING ENDOTHELIAL DYSFUNCTION AND INDICATIONS OF EK

The rationale behind the concept of EK is the replenishment of the structure and function of the innermost corneal layers to achieve corneal dehydration and transparency before the onset of irreversible stromal edema and permanent loss of corneal clarity[8].

The cornea is the anterior-most part of the eye in higher animals, responsible for maintenance of the integrity of the eyeball and transmission of light to the inner structures of the eyes[9]. The endothelium is its innermost layer, derived from the neural crest cells, which migrate underneath the surface ectoderm in three consecutive waves forming the endothelium, corneal stroma and stroma of the iris respectively[10]. In humans, although the endothelium is first discernible at the 5^th week of gestation, the migratory waves begin at the 7^th week and the endothelium is established as a double cuboidal layer, secreting its basement membrane DM by the 8^th week. By the fourth month, tight junctions appear between the apices of corneal endothelial cells, which are responsible for watertightness of the intercellular spaces preventing the entry of aqueous into the corneal stroma, leading to corneal dehydration. Cells later reorganize into a monolayer, and prevention of corneal rehydration is achieved by the active pump-leak function of the endothelial cell membrane. The active transport properties of the membrane proteins represent the ‘pump’ and the stromal swelling pressure represents the ‘leak’[11]. Although the details of this process are controversial, this is the mechanism primarily affected in endothelial dysfunction leading to corneal decompensation[12].

The Donnan-Gibbs equilibrium equation classically described the balance of water and solutes across semi-permeable membranes. Accounting for active transport mechanisms led to the use of Kedem-Katchalsky (KK) equations for explaining the balance of solutes and water across selectively permeable membranes. But these too, did not adequately account for the fixed charges across the membranes. Recent steady-state analyses on active membranes have implied novel pressure dynamics balancing the hydrostatic and osmotic pressures. Hence, recently introduced Enhanced KK equations are proposed to describe the balance of water and ions across complex biological membranes including the corneal endothelium[13].

The dynamic role of the corneal endothelium in maintaining fluid and ion balance with a selective barrier function prevents undue hydration of cornea and loss of stromal fibrillar arrangement thereby maintaining its transparency. The structure and function of the corneal endothelium are irreversibly affected in disorders like Fuch’s endothelial corneal dystrophy (FECD), posterior polymorphous corneal dystrophy, congenital hereditary endothelial dystrophy, glaucoma, iridocorneal endothelial syndrome, aniridia-associated and viral endothelial dysfunction, aphakic bullous keratopathy (ABK) and pseudophakic bullous keratopathy (PBK), as well as due to iatrogenic endothelial damage due to surgical trauma, custom artificial iris implants, glaucoma drainage devices, etc.[8,14,15]. The global prevalence of FECD is up to 7.33% in the adult population, and the incidence of PBK is up to 15% of all cataract surgeries in the long term. These are the most common indications for which EK is performed[16,17].

It is classically known that damaged endothelial cells have very low regenerative potential, lost endothelial cells are not replaced, and the gap thus created is covered by adjacent endothelial cells by cellular enlargement, a process referred to as polymegathism[18]. Specular microscopy may reveal discrete areas of endothelial cell loss (“guttata”), low endothelial cell density (ECD), decreased hexagonality ratio (Hex%), increased polymegathism and pleomorphism (reflected by average cell area and graphs of frequency distribution of cell areas), as well as increased corneal thickness, fluid pockets in the corneal stroma, or even undetectable corneal endothelial morphology due to hazy media, all of which constitute a picture of endothelial dysfunction and are indications for EK when severe and blinding. ECD lower than a certain threshold (400-700/mm² in various circumstances) due to advanced age, fluid currents during intraocular surgery, iatrogenic trauma by instruments or intraocular implant or device [AC intraocular lenses (ACIOLs), glaucoma drainage device (GDD)] etc., may also require replacement of the endothelial layer by EK[19]. Sometimes, the expected cell loss after intraocular surgery (for example, for cataract) superimposed on pre-existing conditions like advanced FECD may result in rapid fall of the ECD to this level. In these cases, EK may be undertaken in conjunction with the intraocular surgery in the same sitting.

Cellular analysis of the DNA of endothelial cells has found that they are arrested in the G1 phase of the cell cycle, and therefore, incapable of division unless the G1 checkpoint is surmounted. Recently, the discovery of the inner transitional zone of the limbal stem cells has led to advent of the understanding that stimulation of peripheral endothelium and activation of these cell-nests can cause regeneration and migration of these cells to replace damaged endothelial cells[20]. Such cases with good peripheral endothelial cell reserve are increasingly being found to be partially or completely reversible with pharmacologic therapy with rho-kinase inhibitors, and several in-vivo cell culture therapies which are under active investigation[8,21]. For example, In FECD, studies on the application of rho-kinase inhibitors (Y-27632, ripasudil, and netarsudil) resulted in improved corneal clarity, ECD, and visual acuity. In PBK, injection of Y-27632 together with cultured corneal endothelial cells into the AC leads to enhanced ECD and improved visual acuity[22]. Thus, the indications of EK are now becoming confined to cases which are not amenable to these non-invasive therapies or where these therapies are unsuccessful or not feasible.

The indications of EK are also limited to the earlier stages of corneal decompensations without significant stromal scarring. In long-standing cases with considerably scarred corneal stroma, the layers are irreversibly distorted and rendered non-transparent, and such cases do not benefit from EK alone and require full-thickness penetrating keratoplasty (PK)[23]. As the anterior corneal layers are reversibly affected in the earlier stages, EK surgeries in general have good visual outcome [Snellen’s best corrected visual acuity (BCVA) in the order of 6/12 on an average]. As the amount of tissue replaced is less compared to full-thickness grafts, rates of rejection are also less. A posterior donor lenticule adds to the net posterior corneal power, thereby causing a hypermetropic shift in the patient’s refractive error[24].

Postoperative interface irregularities are a known cause of poor visual outcome and patient dissatisfaction, thereby requiring replacement of the grafts[24]. Repeat EK procedures also have a lower risk of graft rejection than repeat PK after failed PK[25]. Thus, failed or rejected endothelial grafts are an indication for repeat EK procedures as long as the corneas are not scarred (Video 1).

EK PROCEDURES AND THEIR SIGNIFICANCE

EK procedures can be classified according to the tissues removed and transplanted, as well as the method of dissecting the tissues.

Classically described procedures

Melles et al[26] in 1998 introduced the concept of posterior lamellar keratoplasty, which evolved into DSEK, highlighting the transition from full-thickness keratoplasty to selective endothelial replacement. Terry et al[27] in 2003 explored the early outcomes of EK and coined the term ‘deep lamellar EK’, thereby paving the way for widespread adoption of posterior lamellar techniques. Gorovoy[28] in 2006 defined and standardized DSEK as a surgical technique, emphasizing the importance of donor preparation and the advantages over PK. Price et al[7] in 2005 reported initial long-term outcomes of DSEK, demonstrating the potential for improved visual acuity and faster recovery[7,29]. These early works in the domain of EK provide basis for the understanding of the principles of EK and set the context for further advancements.

Descemet-stripping EK or Descemet’s Stripping automated EK

The technique utilizes dissection of the posterior-most 100-130 microns of donor corneal tissue manually or by use of an automated microkeratome respectively, thereby providing a donor lenticule consisting of the endothelium, DM and some amount of pre-Descemet tissue for transplantation. Anterior segment optical coherence tomography (OCT) after a successful procedure clearly demonstrates a thicker donor lenticule attached to the posterior stroma, with posterior tamponade by the residual gas bubble in the AC. Thus, although descemet-stripping EK (DSEK) yields a thicker graft, but this is the simpler procedure with an easier learning curve.

Descemet membrane EK

Descemet membrane EK (DMEK) is the more physiological endothelial cell replacement technique. It consists of transplantation of only the donor DM-endothelium complex. Its reproducibility, and quick and near-complete visual recovery make DMEK the procedure of choice in experienced hands. DMEK allows predictable refractive outcomes with a decreased risk of allograft rejection. However, thinner grafts imply tighter scrolls. Sourcing tissue from older donors with scrolls relatively lesser tight make the procedure easier, allowing better graft unfolding with limited manipulation-induced endothelial cell loss. The functional outcomes with older donor grafts are comparable with younger donor grafts[30].

Modern-day graft delivery techniques range from using a Pasteur glass pipette to an intraocular lens injector cartridge. Graft unfolding and attachment techniques vary depending on the configuration of the DMEK roll post-injection into the AC. Symmetric double Descemet roll curl facing up is the desired outcome. Asymmetric DMEK rolls can be handled by different surgical maneuvers like the Dirisamer technique, Dapena maneuver, or single sliding cannula maneuver[31].

Comparison of DSEK/ Descemet’s Stripping automated EK and DMEK

Difficulty in tissue handling due to extremely thin graft makes DMEK challenging and the learning curve steep[32]. Theoretically, excessive graft manipulation during surgery and subsequent multiple reinjections of gas tamponade (“re-bubbling”) result in primary graft failure which is more frequently expected for DMEK[33]. However, systematic review of contralateral-eye studies of DSEK and DMEK showed low-certainty evidence that DMEK provides some advantage in terms of final BCVA, with very low-certainty evidence of more graft dislocations needing repositioning and air injection surgeries. For DMEK, 6% perfluoropropane (C3F8) gas was found to be better than 20% sulfur hexafluoride (SF6) as a tamponade agent, as it was associated with lower odds of need for re-bubbling following graft detachment, whereas no such difference was found for DSEK[34]. Less postoperative hypermetropia and less higher order aberrations are the only benefits of Descemet’s Stripping Automated EK (DSAEK) over DMEK[35]. Even when compared with modern techniques like DSAEK or Ultrathin-DSAEK, DMEK provides better visual recovery (with up to three-fourths achieving 6/7.5 within 1-3 months) and comparable short to intermediate term endothelial cell loss (6-12 months)[36-40]. More patients are satisfied after DMEK than DSAEK[41]. Standardization of the surgical technique decreases the rate of postoperative complications and makes the procedure more predictable[42].

In the long term (5 years following the transplantation), DMEK eyes with FECD had better visual acuity outcomes compared with DSEK. The rates of graft survival and endothelial cell loss in eyes with FECD were similar, whether the initial procedure was DSEK or DMEK[43]. Although DMEK had significantly lower risk of immunologic rejection than DSEK, rejection episodes rarely resulted in graft failure within 5 years with either procedure[44]. According to a meta-analysis, endothelial cell loss was lower in "endothelium-in" DMEK at 6 months compared to "endothelium-out"[45]. There is statistically significant difference in the cumulative risk of long term graft failure (up to 10 year): DMEK 5%, DSEK 11%, and PK 19%[44].

The key comparative studies including randomized controlled trials of various EK procedures are provided in Table 1[46-52]. Table 2 summarizes key comparative and non-comparative studies reporting the outcomes of EK procedures in various clinical scenarios[43,53-58].

Table 1 Summary of key prospective comparative studies and randomized controlled trials reporting the outcomes of endothelial keratoplasty procedures.

Ref.	Publication	n	Study design	Indication	Intervention	Summary
Stuart et al[46], 2016	Cochrane Database of Systematic Reviews	72	Non-randomized, paired, contralateral-eye study	FECD and PBK	DMEK vs DSAEK	DMEK may provide better visual acuity than DSAEK for corneal endothelial failure, but with more graft dislocations
Dunker et al[47], 2020	Ophthalmology (Rochester, Minn)	54	Prospective, multicenter randomized controlled trial	FECD	DMEK vs UT-DSAEK	DMEK and UT-DSAEK corneal endothelial transplantation procedures have similar visual acuity and endothelial cell density outcomes
Dickman et al[48], 2016	Ophthalmology (Rochester, Minn)	66	Multicenter, prospective, double-masked, randomized, controlled clinical trial	FECD	UT-DSAEK vs DMEK	Ultrathin Descemet stripping automated endothelial keratoplasty (UT-DSAEK) results in faster and better visual acuity recovery compared to standard DSAEK
Matsou et al[49], 2021	Cornea	56	Prospective, double-blinded randomized controlled clinical trial	FECD	MT-DSAEK vs DMEK	DMEK surgery resulted in significantly better visual acuity compared to MT-DSAEK for treating Fuchs dystrophy-related corneal decompensation
Chamberlain et al[50], 2019	Ophthalmology (Rochester, Minn.)	38	Randomized, controlled, patient- and outcome-masked clinical trial	FECD and PBK	DMEK vs UT-DSAEK	DMEK had superior visual acuity results compared to UT-DSAEK for treating corneal endothelial dysfunction
Shanmugam et al[51], 2023	Cornea	28	Prospective, randomized, interventional study	Corneal Decom-pensation	PDEK vs DMEK	PDEK and DMEK procedures showed comparable visual and graft survival outcomes in endothelial decompensation
Agarwal et al[52], 2017	Canadian Journal of Ophthalmology	6	Prospective, single-centre, interventional case series	PBK	PDEK and DMEK	EK with epithelial debridement performed for the treatment of chronic PBK resulted in significantly improved visual acuity to a functional level, with the clearance of subepithelial fibrosis and anterior stromal scar, in most patients

DMEK: Descemet membrane endothelial keratoplasty; UT-DSAEK: Ultrathin Descemet stripping automated endothelial keratoplasty; DSAEK: Descemet stripping automated endothelial keratoplasty; FECD: Fuchs endothelial corneal dystrophy; PBK: Pseudophakic Bullous Keratopathy; PDEK: Pre-Descemet Endothelial Keratoplasty; MT-DSAEK: Microthin Descemet Stripping Automated endothelial Keratoplasty.

Table 2 Summary of comparative and non-comparative studies reporting the outcomes of corneal endothelial transplant procedures in various clinical scenarios.

Ref.	Publication	Study design	Study duration	Study participants	Survival outcomes
Fu et al[43], 2024	Cornea	Retrospective clinical cohort study	10 years	356 (DSEK), Indication: 209 (FECD), 88 (bullous keratopathy), 39 (previous graft failure)	Overall, DSEK has a 79% 10-year graft survival rate (including complex grafts), with higher rates for Fuchs endothelial dystrophy (92%), despite significant endothelial cell loss
Woo et al[53], 2019	American Journal of Ophthalmology – Glaucoma	Retrospective comparative cohort study	27 years	121 eyes (DMEK), 423 eyes (DSAEK), 405 eyes (PK), for a total of 949 eyes from patients with FECD, and BK	DMEK (97.4%) has better long-term graft survival and lower complication rates compared to DSAEK (78.4%) and PK (54.6%)
Price et al[54], 2011	Ophthalmology (Rochester, Minn.)	Retrospective interventional case series	5 years	165 eyes (147) (89%)-FECD and 18 eyes (11%)-PBK and ABK]	Five-year graft survival and endothelial cell loss after Descemet's stripping endothelial keratoplasty are comparable to penetrating keratoplasty
Birbal et al[55], 2020	Cornea	Retrospective interventional case series	5 years	500 eyes of 393 patients. Indications: FECD, Bullous keratopathy, failed grafts	5 Five-year graft survival probability in 0.90 with 82% achieving > 20/25
Deng et al[56], 2018	Ophthalmology (Rochester, Minn.)	Systematic review	Follow-up ranged from 5.7 to 68 months		DMEK is a safe and effective treatment for corneal endothelial dysfunction, with better visual outcomes and lower refractive error compared to DSEK
Kang et al[57], 2019	Journal of Glaucoma	Retrospective case series	Mean follow-up of 36.5 ± 31.4 months	83 patients who underwent 122 DSEK procedures on 85 eyes	DSEK after glaucoma drainage device implantation has high graft failure rates and adverse effects on long-term graft survival
Baydoun et al[58], 2015	JAMA Ophthalmology	Retrospective cross-sectional studies	Approximately 9 years, from August 8, 2006 to June 17, 2015, with endothelial survival followed for up to 8 years after the DMEK procedures	352 eyes, with 314 -FECD, 31 eyes-bullous keratopathy, and 7 eyes -failed previous endothelial grafts	Endothelial survival after Descemet membrane endothelial keratoplasty is better in eyes with Fuchs endothelial corneal dystrophy and completely attached grafts compared to eyes with bullous keratopathy and partially detached grafts

DMEK: Descemet membrane endothelial keratoplasty; DSAEK: Descemet stripping automated endothelial keratoplasty; PBK: Pseudophakic bullous keratopathy; ABK: Aphakic bullous keratopathy; FECD: Fuch’s endothelial corneal dystrophy.

Recent advances

In the present scenario where there is already a paucity of optical-quality corneal tissues, high utilization rates are necessary and one cannot afford to risk losing any corneal graft[59]. Thus, modern methods of graft preparation have evolved, such as the use of eccentric posterior lamellar punches on the donor cornea. A 2.4% increase in the availability of DMEK-suitable corneas can be achieved by offsetting the punch to achieve a clear central zone[60]. Variations in the size and shape of the graft can lead to utilization of one graft in multiple recipients - the so-called hemi-DMEK, quarter-DMEK or ¾-DMEK based on the transplanted area in relation to the total graft size. These customized grafts may be challenging to prepare and position, but offer excellent outcomes on implantation[61,62]. For example, the outcomes of quarter-DMEK in central FECD are similar to conventional DMEK, but with only a quarter of the total graft transplanted, potentially quadrupling the graft availability[63].

In addition, the following modern non-DMEK surgeries have evolved, which offer good surgical outcomes and have been found reproducible even in the hands of less experienced corneal surgeons.

Ultrathin DSAEK

In ultrathin DSAEK (UT-DSAEK), also called Microthin DSAEK, thinner grafts offer the advantage of DMEK by inducing minimal hyperopia, and at the same time provide ease of handling the tissue like conventional DSAEK. No significant difference has been noted in the corrected visual acuity, hyperopic shift, and endothelial cell loss compared to DMEK[64,65]. In fact, adverse events have been noted to be more common in the DMEK group. Literature suggests manual dissection, double pass, and single pass techniques to obtain UT-DSAEK grafts.

Double pass technique: Hsu et al[66] mentioned using 200 microns head for the first pass followed by 90/110/130 microns head for the second pass depending upon the residual stromal bed thickness to obtain < 100 microns DSAEK grafts. It is emphasized that the second pass should be slow to obtain smoother and thinner grafts. To get thinner grafts, corneas with < 550 microns central thickness are preferred. There are different techniques discussed in the literature to deturge the cornea before subjecting them to single-pass. Use of THIN-C media, before graft preparation is termed OSMO-UT-DSAEK. The preconditioning with THIN-C media facilitates a significantly improved smooth interface[67]. Other techniques to get thinner grafts include high pressures in the artificial AC[68], directing sterile airflow over stroma, and desiccating corneal stroma using a polyvinyl-soaked sponge before microkeratome cut[69].

Single-pass technique: Though the double-pass technique facilitates thinner grafts; however, the risk of increased endothelial cell loss and perforation of the graft led to the evolution of single-pass techniques[70]. Vajpayee et al[71] demonstrated slow and safe ultrathin DSAEK graft harvesting techniques using the 400 microns head of the automated microkeratome. In a recent study by Sharma et al[72] endothelial cell loss was found to be comparable between single-pass and double-pass techniques.

Koo et al[73] in their retrospective analysis evaluated the refractive outcomes of UT-DSAEK combined with phacoemulsification and IOL implantation. Good visual acuity was achieved 12 months postoperatively. ECD remained stable with no significant loss from baseline. The study concluded that ‘UT-DSAEK triple’ surgery produces favorable visual and refractive outcomes, though a hyperopic shift of 1.00 to 2.00 diopters should be anticipated[73]. Similarly, with triple-DMEK, an expected -0.50D to -1.00D refractive target should be entered while calculating IOL power[74,75].

Nano-thin DSAEK

This uses standard nomograms to obtain thinner grafts < 50 microns. The technique was found to be safe with minimal endothelial cell loss compared to DMEK and UT-DSAEK[76].

Pre-Descemet’s EK

The collagenous Pre-Descemet’s layer (PDL) is named Dua’s layer and novel insights have emerged regarding its role in improving EK outcomes. It has been shown that including the PDL in the posterior lenticule allows easier insertion and handling of EK lenticules compared to DMEK, as the PDL could act as a splint for DM and endothelium[77]. This information was utilized to evolve a novel surgical technique, termed Pre-Descemet’s EK (PDEK)[78]. The formation of a type 1 big bubble (BB) in the donor cornea dissects through the cleavage plane anterior to the Dua’s layer adding only about 20 microns of thickness. The posterior lenticule, thus consisting of PDL, DM and Endothelium together, is inserted into recipient eyes and gas injected similar to DSEK or DMEK. But due to the splinting effect, PDEK tissue scrolls less than DMEK tissue, and can thus be sourced from younger eyes with higher ECD, enhancing outcomes[79]. In a recent prospective, randomized, interventional study, PDEK was found to be comparable to DMEK for qualitative and quantitative visual outcomes and graft survival[80].

Microkeratome and excimer-laser assisted EK

In an effort to reduce the graft-host junction irregularities, Microkeratome and Excimer-laser assisted EK (MELEK) was introduced as a modified form of UT-DSAEK. MELEK is a recent innovation wherein the corneal graft is prepared by a single cut of an automated microkeratome, followed by stromal excimer-laser thinning and smoothing[81].

Femtosecond-DSEK, and FELEK

Femtosecond (FS) laser accurately prepares 7-9.5 mm posterior corneal stromal lenticules of 150 to 200 microns[82]. The preliminary results of FS laser-assisted DSAEK were encouraging[83]. However, the visual outcome was limited compared to PK and DSAEK due to an increase in irregular astigmatism caused by posterior surface irregularities[84].

The microkeratome in MELEK has been recently replaced by the FS-laser in FELEK, where FS-laser graft dissection is followed by excimer laser smoothening of the graft. FS laser facilitates thin and consistent graft cuts with accuracy, whereas excimer laser smoothens the interface improving the vision quality[85]. The microkeratome gives a smoother surface, but inflammation is less with femtolaser[86]. A summary of key recent studies related to FS-laser EK is presented in Table 3[87-90]. Figure 1 shows the indications of various EK procedures, and a flowchart for the choice of EK procedures in various clinical scenarios is shown in Figure 2.

Figure 1 Indications of Endothelial Keratoplasty procedures. FECD: Fuch’s endothelial corneal dystrophy; CHED: Congenital hereditary endothelial dystrophy PPCD: Posterior polymorphous corneal dystrophy; PBK: Pseudophakic bullous keratopathy; ABK: Aphakic bullous keratopathy; PK: Penetrating keratoplasty; EK: Endothelial keratoplasty; TASS: Toxic anterior-segment syndrome; ICE: Iridocorneal Endothelial; HSV: Herpes simplex virus; CMV: Cytomegalovirus.

Figure 2 Choice of endothelial keratoplasty procedures in various clinical scenarios. PK: Penetrating keratoplasty; EK: Endothelial keratoplasty

Table 3 Comparison of outcomes of femtolaser-assisted endothelial keratoplasty procedures with conventional manual procedures.

Ref.	Topic	Graft survival and graft-related complications	Visual Outcomes
Malyugin et al[87], 2019	FS-DSEK vs DSAEK	The graft survival was 89.5% in the femtosecond laser-assisted DSEK (FS-DSEK) group and 95% in the microkeratome-assisted DSAEK group, but the endothelial cell loss was higher in the FS-DSEK group compared to the DSAEK group at 12 months	The visual acuity outcomes were similar between the two groups at long-term follow-up
Einan-Lifshitz et al[86], 2017	FS-DMEK vs Manual DMEK (M-DMEK)	The graft survival, as indicated by the endothelial cell loss (24% vs 29%) and graft detachment rates (0% vs 20%), was better in the FE-DMEK group compared to the M-DMEK group
Sorkin et al[89], 2020	F-DMEK and M-DMEK	Significantly lower rates of graft detachment (6.25% vs 35.6%) and need for rebubbling (6.25% vs 33.3%) in the F-DMEK group 3) Significantly lower rates of endothelial cell loss in the F-DMEK group at 1 and 2 years, 4) Numerically lower graft failure rate in the F-DMEK group (0% vs 8.9%), though not statistically significant	Comparable visual acuity improvement between F-DMEK and M-DMEK groups over 3 years
Cheng et al[90], 2009	FL-EK and PK	Mean postoperative BCVA was 20/70 ± 2 lines in the FLEK group and 20/44 ± 2 Lines in the PK group (P < 0.001), but the gain in the best corrected visual acuity between the two groups was not significantly different. The endothelial cell loss in the FL-EK and PK group was 65 ± 12% and 23 ± 15% (P < 0.001)	FL-EK reduces postoperative astigmatism but has higher endothelial cell loss compared to PK

FS: Femtosecond; FL: Femtosecond laser; PK: Penetrating keratoplasty; BCVA: Best corrected visual acuity; DMEK: Descemet membrane endothelial keratoplasty; DSAEK: Descemet stripping automated endothelial keratoplasty.

SPECIAL SITUATIONS NECESSITATING TAILORED EK APPROACHES

In certain cases, EK requires strategic modifications to address unique patient needs or complex ocular conditions. Patient-related factors, including age and systemic or ocular comorbidities, significantly influence the outcomes of EK[91]. Older patients often present with reduced corneal ECD, which may predispose them to higher graft failure rates and slower visual recovery post-surgery. Moreover, systemic diseases such as diabetes mellitus can adversely affect endothelial cell metabolism and healing, leading to a higher likelihood of complications such as graft rejection or failure.

Pre-existing ocular conditions like glaucoma, previous glaucoma surgery (e.g., trabeculectomy or GDD), and ocular surface diseases (e.g., dry eye syndrome, meibomian gland dysfunction) introduce complexities in EK. These factors can compromise graft adherence, alter intraocular pressure (IOP) dynamics, and necessitate tailored surgical modifications to optimize outcomes[92]. For instance, GDD may lead to uneven aqueous flow, increasing the risk of graft detachment, whereas trabeculectomy blebs can cause hypotony-related complications[93].

Furthermore, eyes with prior ocular surgeries, including cataract extraction or retinal detachment repair, exhibit altered AC anatomy and pose additional challenges in graft placement and stability[60]. Patients with severe ocular surface diseases require intensive preoperative management, such as control of inflammation and optimization of the tear film, to enhance graft survival.

Understanding the interplay of these factors is critical for improving EK success rates. Comprehensive preoperative assessment and multidisciplinary collaboration between corneal surgeons and specialists in glaucoma, retina, and systemic diseases can help mitigate risks and tailor interventions to individual patient profiles. These approaches ensure better surgical outcomes and patient satisfaction, highlighting the necessity of integrating patient-related factors into surgical planning and postoperative care. Tailored approaches also help to minimize complications and need for second surgeries in such complex cases[94,95].

EK in eyes with prior intraocular surgeries

Eyes with prior multiple intraocular surgeries may present significant challenges due to altered anatomy, corneal scarring, or compromised corneal morphology[93]. In such cases, DMEK may be less favorable, and surgeons might opt for DSAEK or DSEK, in which a thicker graft provides more stability[96]. For example, Woo et al[97] have described a controlled 'pull-through' technique of donor insertion in the 'endothelium-in' configuration using DSAEK-prepared donor stroma as carrier and the EndoGlide Ultrathin DSAEK donor insertion device, which may be useful especially in complicated eyes - the so-called ‘Hybrid-DMEK’ or ‘Tri-folded endothelium-in DMEK’, the 3-year outcomes of which have been reported to be satisfactory[97,98].

Vitrectomy

Eyes that have undergone prior vitrectomy pose unique challenges for EK due to the absence of vitreous, which typically provides structural support to the posterior segment[99]. In these eyes, the altered anatomy can cause issues with IOP regulation and graft adherence.

Romano et al[100] examined the techniques, complications, and outcomes of DMEK in aphakic, aniridic, and vitrectomized eyes by conducting a literature search of relevant studies. Mean rebubbling rate was 29% and mean endothelial cell loss was 37% at 6 months. Postoperative visual acuity improved significantly, from 1.47 to 0.7 LogMAR. Thus, despite the complexities associated with these cases, DMEK remains a viable treatment option for managing endothelial decompensation in such challenging eyes, with outcomes similar to non-complex cases[100]. In the absence of vitreous support, graft dislocation can occur more easily. To overcome this, techniques such as proper graft positioning using equatorial indentation or repeated tapping, increasing the air bubble tamponade time or using heavier gases (e.g., C3F8) to can help maintain the graft in position. Some surgeons may also place sutures to secure the graft in difficult cases[62,101].

ACIOLs

In eyes with ACIOLs, the AC may be shallower, leading to a higher risk of graft detachment and difficulty in maintaining proper positioning after EK. The presence of an ACIOL can also limit access to the posterior corneal surface. To address these challenges, surgeons may need to frequently inject heavy cohesive viscoelastic devices to maintain AC depth. Additional care is taken to avoid graft manipulation against the lens. In certain cases, exchanging the ACIOL for a posterior chamber intraocular lens (PCIOL, e.g., retro-fixated iris-claw IOL or scleral-fixated IOL) may be recommended to optimize outcomes.

Woo et al[102] in their retrospective comparative cohort study evaluated long-term outcomes of DSAEK in eyes with pseudophakic or ABK. Graft survival was significantly higher in secondary PCIOL group than in ACIOL group over a 5-year period. ACIOL was identified as a risk factor for graft failure. PCIOL subluxation or dislocation occurred in 9.3% cases. The study concluded that IOL exchange to secondary PCIOL improves graft survival in patients undergoing DSAEK and is recommended for better long-term outcomes in eyes with ACIOL[102].

Glaucoma filtration surgery

In patients with GDDs, altered AC dynamics increase the risk of graft detachment. The presence of a tube in the AC may lead to irregular flow of aqueous humor, making it difficult for the graft to adhere properly to the cornea[92]. Surgical adjustments include positioning of the graft to avoid contact with the tube, strategic air bubble placement and longer air tamponade to support graft attachment. The ¾-DMEK technique offers promise by avoiding replacing the endothelium in the area of the tube[62]. In some cases, repositioning the tube or revising the device may be necessary to optimize graft success[103].

Birbal et al[103] in their retrospective case series in eyes with a GDD along with bullous keratopathy, failed transplants, or Fuchs endothelial dystrophy, showed a cumulative graft survival rate of 89% at 1 year, with 73% of eyes showing significant improvement in BCVA. ECD decreased by 37%, 60%, and 71% at 1, 6, and 12 months, respectively. Postoperative complications included graft detachment requiring rebubbling (22%), allograft rejection (9%), secondary graft failure (9%), and cataract formation in phakic eyes (33%). Despite acceptable visual outcomes, the presence of a GDD may reduce graft survival and increase the likelihood of re-keratoplasty. Surgical modifications are necessary to optimize outcomes in these complex cases[103].

Eyes that have undergone trabeculectomy pose challenges for IOP management post-EK, as maintaining an optimal balance between IOP and graft integrity is critical. There is a risk of over-filtration, which can lead to hypotony and subsequent graft detachment. Careful preoperative evaluation and coordination between the glaucoma and corneal surgeons are essential. Strategies like adjusting bleb function, monitoring for hypotony, and possibly modifying bleb morphology are critical. Postoperative IOP control through the judicious use of medications or further interventions may be needed to maintain both graft survival and effective IOP management[92]. Aldave et al[104] evaluated outcomes of DSEK in 101 eyes with previous glaucoma surgery. There was a higher rate of endothelial rejection (12.9%) and significantly higher rates of secondary graft failure (15.9%) compared to those without surgery (3.2%). Primary graft failure (4.4%) and donor dislocation (14.2%) in eyes with prior glaucoma surgery were not significantly different from eyes without glaucoma surgery[104].

EK in pediatric patients

Performing EK in pediatric patients is a rare but challenging scenario due to anatomical, physiological, and behavioral factors. The smaller anatomical size of the cornea and AC in pediatric eyes requires the surgeon to adapt their techniques to accommodate the dimensions to reduce the rate of endothelial cell loss in pediatric eyes. The increased elasticity of tissues in children complicates graft handling, making it more prone to shifting or detachment during and after surgery. Pediatric eyes also exhibit a higher risk of graft rejection due to a more robust immune response. The growing and dynamic nature of the pediatric eye can make long-term outcomes less predictable, with an increased chance of graft failure over time compared to adult patients[105]. Additionally, pediatric patients have a higher risk of amblyopia, which necessitates expedited visual rehabilitation.

Preoperative planning should be meticulous, and include accurate biometry and imaging (e.g., anterior segment OCT), essential for assessing corneal thickness and AC depth. Surgeons must consider tailored graft sizing and precise manipulation to ensure proper graft positioning and attachment. Enhanced postoperative care, including vigilant monitoring for signs of rejection and prompt management of complications, is crucial for improving outcomes in this challenging patient population[106].

Pediatric EK is typically performed under general anesthesia due to poor cooperation during surgery, hence fitness for general anesthesia has to be obtained after thorough evaluation for systemic comorbidities. Donor tissues with higher ECD are preferred to accommodate accelerated cell loss. Postoperatively, pediatric patients often require intensive postoperative monitoring due to poor compliance with medications. Adjunct therapies, such as amblyopia treatment with patching or penalization, may be needed to optimize visual outcomes.

Ramappa et al[107] evaluated the outcomes of 180 DSAEK procedures in managing corneal endothelial disorders in children under 14 years of age. At a median follow-up of 2.5 years, about 86% of grafts were clear, and BCVA significantly improved. Long-term graft survival rates were 93%, 87%, and 78% at 1, 3, and 7 years, respectively. Significant risk factors for graft failure included the indication for DSAEK, age at surgery, and subsequent interventions. Endothelial cell loss was 40% at 6 months and increased to 62% at 7 years, necessitating long-term monitoring[107].

EK in eyes with complex anterior segment abnormalities

Patients with complex anterior segment anatomy-such as those with failed prior grafts, aphakic eyes, trauma or aniridia-may benefit from customized surgical techniques to ensure adequate graft positioning and adhesion[108]. Planning according to the pre-existing anterior segment anomalies, such as a shallow AC, anterior synechiae and peripheral scars is essential, as these can complicate graft placement[94]. Techniques such as performing peripheral or sectoral iridectomy or adjusting graft size may help ensure proper positioning and adhesion.

Post-traumatic eyes

Post-traumatic eyes present unique challenges due to altered anatomy, extensive scarring, and irregularities in the corneal or anterior segment structure. Peripheral corneal scarring and anterior segment irregularities complicate graft attachment and successful surgery. Procedural considerations include comprehensive preoperative imaging, including ultrasound biomicroscopy and anterior segment OCT or Scheimpflug imaging, crucial for identifying structural abnormalities and planning surgery[109].

Ensuring proper graft adhesion in eyes with altered AC dynamics can be difficult. Irregular recipient beds can lead to poor graft adhesion or malposition. In these cases, customized preparation of donor tissue is essential to fit the irregular surface precisely, improving the chances of successful integration[110]. Modified techniques of graft preparation, such as smaller-diameter grafts or pre-stripped DMEK grafts, may be required for irregular anterior segments. Techniques like venting incisions or air-fluid exchange are often employed to optimize graft placement.

Previous surgical interventions, such as scleral buckles or ACIOLs, may further complicate the surgical approach. In addition, traumatized eyes are at higher risk for graft rejection and failure. Immunosuppressive therapy and careful wound closure are critical in these cases.

Aphakic eyes

Lack of lens support poses significant risks for graft detachment due to altered AC dynamics, making it difficult to maintain graft position and attachment. In such cases, use of viscoelastic materials, careful graft manipulation, and even modified suturing techniques, are employed to secure the graft in place, ensuring successful postoperative recovery. Karadag et al[111] described a novel technique for DMEK in aphakic and vitrectomized eyes using a temporary stromal barrier created from the donor tissue placed over the iris to close the pupil. Thus, AC stability was maintained and graft dislocation was prevented. After graft attachment with air tamponade, the barrier was removed, and the AC was refilled with air. The technique resulted in a successful outcome with no complications during the 1-month follow-up[111].

EK in corneal ectatic disorders

Patients with both FECD and keratoconus represent a complex challenge in corneal surgery due to the presence of two distinct pathologies-endothelial dysfunction and corneal thinning. FECD causes progressive endothelial cell loss, resulting in corneal edema, while keratoconus leads to structural weakening and ectasia, or bulging of the cornea[112]. The dual nature of this condition requires a tailored approach in surgical planning and execution[113]. The corneal thinning seen in keratoconus can exacerbate the difficulty of performing EK, as the tissue may be more fragile. Additionally, the altered corneal structure could complicate the proper positioning and adhesion of grafts. Therefore, preoperative assessment must include pachymetry and topography to evaluate the extent of both conditions and guide surgical decisions, with emphasis on posterior corneal surface mapping[114].

In patients with significant corneal thinning, a combined surgical approach may be warranted. While EK can be used to address endothelial dysfunction, it might not fully correct the irregular corneal shape caused by keratoconus. In such cases, hybrid procedures may include combining EK with deep anterior lamellar keratoplasty to improve both endothelial function and corneal stability without resorting to an open-globe approach. These tailored approaches offer a comprehensive solution for restoring corneal clarity and refractive stability in this complex patient population[112].

EK in ocular surface disorders

Patients with ocular surface diseases, such as severe dry eye or conjunctival scarring, or Stevens-Johnson syndrome, may require extensive preoperative and postoperative management to optimize the ocular surface for graft survival[115]. The risk of ocular surface diseases arising out of continuous and prolonged use of multiple topical medications necessitates preference to pH-balanced and preservative-free formulations of drugs wherever feasible. Systemic inflammatory causes commonly associated with uveitis causing endothelial decompensation must also be controlled prior to replacing the endothelium.

EK in glaucoma

Eyes with pre-existing glaucoma may need particular attention to IOP management pre- and post-operatively, as endothelial graft function can be compromised by increased pressure[116]. In a study by Patel et al[117], overall graft survival in cases which underwent DSEK was 85%, 75%, and 71% at 5, 10, and 12 years, respectively. However, in cases of FECD without glaucoma, the survival was 95%, 89%, and 87%, respectively[117]. Meticulous postoperative IOP monitoring and potential adjustments to IOP-lowering medications are necessary. Preoperative glaucoma heightens the possibility of graft failure or rejection after DSEK, and the requirement for a glaucoma surgery in the next 10 years[117].

Repeat EK in complex cases with failed grafts

For patients who experience graft failure following an initial EK, re-grafting may be necessary. When considering repeat EK, several factors need to be evaluated, including the health of the recipient's corneal stroma and the cause of the graft failure. In cases of failed prior keratoplasty, repeat EK procedures, like ‘triple DMEK’ (graft replacement and cataract extraction), may be performed, but with an increased risk of graft rejection or failure. Similarly, modern DSEK modifications can also be combined with cataract extraction.

Success rates for repeat procedures can be slightly lower compared to primary EK due to the challenges of a previously operated cornea and potential complications like graft rejection or failure to attach. Modifications in tissue preparation, such as the use of thinner grafts or changes in donor tissue quality, and adjustments in surgical technique, such as enhanced graft insertion methods, can improve outcomes[118].

In cases where DSAEK has failed, transitioning to DMEK may be indicated for repeat procedures. DMEK offers a more precise restoration of the endothelial layer due to its thinner graft, which can result in better visual outcomes and lower rejection rates. However, careful patient selection and thorough preoperative assessment are critical when transitioning to DMEK, as the surgical learning curve and tissue handling are more challenging than DSAEK[33].

Preoperative evaluation, patient counseling and postoperative care

In the aforementioned special situations, detailed preoperative evaluation is essential to determine both anatomical and functional suitability for EK. This involves assessing the condition of the eye as a whole, with emphasis to the effects of any previous ocular surgeries or comorbid conditions[119]. Setting realistic expectations for outcomes by discussing with the patient about potential complications, longer recovery times, and the possibility of needing further interventions in the future, is equally important[120].

Procedural decisions for successful outcomes in complex cases include consideration of device-assisted graft delivery. In both pediatric and post-traumatic cases, devices such as the Tan EndoGlide or EndoSerter may facilitate graft insertion and reduce trauma to the anterior segment. Intraoperative use of viscoelastic agents or fibrin glue can assist in stabilizing the graft, thereby improving outcomes. Hybrid techniques combining DSEK with anterior segment reconstruction, such as iridoplasty or lens exchange, may be necessary to address concurrent anatomical defects.

Postoperative care in these complex cases requires careful management of IOP and immune responses to prevent graft failure or rejection. Monitoring for early signs of graft detachment, increased IOP, or immune-mediated reactions is crucial. Prolonged follow-up is often necessary to ensure graft adherence, maintain visual outcomes, and manage any complications that arise, such as increased pressure in eyes with GDD or immune rejection in pediatric cases. Adjustments in medical management, including immunosuppressive therapies and IOP-lowering agents, may also be required[121].

Future directions

Advanced imaging modalities, such as intraoperative OCT, can guide surgical planning and intraoperative decisions in complex cases. Artificial intelligence (AI) models are emerging as tools to predict surgical complexity and outcomes, offering further precision in tailoring treatment plans. Additionally, newer techniques, such as bioengineered corneal tissues, hold promise for overcoming challenges in these difficult cases.

MODERN INSTRUMENTATION FOR EK

Advances in instrumentation and novel utilization of existing instruments have allowed for more accurate dissection of graft and host tissue, allowing a new level of customization and precision never seen before.

Pereira et al[122] have used a scoring technique wherein the Sinskey hook is used to score the donor corneoscleral disc from the endothelial side. Saint-Jean et al[123] have described another modification where a blunt instrument is used to score the region of the Schwalbe’s line circumferentially. A PDEK Clamp has been described by Dua and Said, which enables good handling of donor sclerocorneal disks, allows air to be injected in the corneal stroma and shuts the fenestrations in the periphery of the PDL thereby preventing escape of air[124]. The modifications have been described as more reliable techniques for creating a type 1 BB consistently to enhance graft utilization and outcome.

Yury et al[125] have described a surgical innovation named ‘Modified Kalinnikov-Dinh surgical technique for donor’s graft preparation in which the donor corneoscleral button is fixed onto the base using four 30G needles for PDEK, and the BB is created using a PDEK ring. The authors have also proposed Optimized Kalinnikov-Dinh technology for PDEK graft preservation, wherein the partially fixed corneoscleral tissue is moved to the preservation container for later use[125]. These procedures are likely to facilitate the widespread use of PDEK grafts owing to the availability of relatively easy-to-handle readymade grafts.

The Tan EndoGlide (AngioTech, United States) has replaced the traditional Busin glide, used to taco-fold the donor lenticule to allow it to be inserted into the AC atraumatically through a small incision. The endoglide forms a closed chamber when inserted into the AC, thereby preventing shallowing of the AC, reducing the mechanical shear on the graft and the associated endothelial loss[126]. The device requires special forceps to pull the graft into the AC from a nasal paracentesis.

Similar to the EndoGlide, the EndoSerter (Ocular Systems Inc, United States) enables rolling (instead of folding) of the lenticule, reducing endothelial cell loss. Self-deployment of the donor lenticule into the AC is facilitated by a stable AC maintained by direct flow of balanced salt solution into the device and withdrawal of the delivery scaffold once the device is fully inserted[127].

Novel use of air continuously flowing into the AC through an AC maintainer connected to the air pump of newer phacoemulsification machines or using the fluid-air exchange system present in posterior vitrectomy systems, has been recently introduced by Jacob et al[128]. It is an innovative method of maintaining the AC during PDEK procedures in complicated situations. Air-pump assisted DMEK allows ease of descemetorhexis, and prevention of bleeding during peripheral iridectomy and synechiolysis. It prevents oozing of blood from peripheral corneal neovascularization into the AC. It also assists in accurate graft maneuvering, unfolding and flattening, leading to quicker graft adhesion and reduced risk of graft detachment in the post-operative period[128]. Reduced risk of graft detachment is also seen with a further improvement of this technique involving the use of host DM or the corneal incision for graft scaffolding. The descemetorhexis is created in opposite quadrants, and after insertion of the graft, the host DM is gently teased out from under the graft. The host DM is then released to overlap the graft posteriorly, providing a scaffold. As an alternative, one edge of the graft is gently pulled to lie firmly into the corneal incision between the two lips of the entry wound[129]. Graft detachment risk has also been shown to reduce to 0% after presoaking donor cornea in balanced salt solution Plus (Alcon, Fort Worth, Texas, United States)[130].

Recently, the advent of microscope-integrated intra-operative OCT (MIi-OCT) has opened a new dimension in surgical precision during dissection of recipient and donor tissue as well as donor tissue positioning in the recipient. It consists of a live display of cross-sectional OCT scans of a designated area being focused through the operating microscope. Adjustment of on-display cross-hairs allow the device to display different areas of the surgical field. MIi-OCT guided PDEK has been termed i-PDEK, and is one of the newest types of EK[131].

Role of AI in advancing EK outcomes

AI particularly holds transformative potential in revolutionizing the field of EK. AI-powered algorithms can analyze large datasets from OCT, specular microscopy, and other imaging modalities to enhance preoperative planning and patient selection[132]. By identifying subtle patterns in corneal pathology, AI can assist surgeons in determining optimal candidates for EK, thereby improving surgical outcomes[133].

In addition, AI-driven predictive models can integrate data from patient demographics, comorbidities, and previous ocular surgeries to forecast potential complications or graft survival probabilities[134]. For instance, machine learning algorithms could assess the impact of factors such as age, history of glaucoma surgery, or ocular surface disease on graft adherence and long-term viability, enabling surgeons to tailor surgical strategies accordingly[135,136]. AI-guided analysis of EK grafts can enhance outcomes by introducing automation and objectivity to the graft assessment process[137].

Postoperatively, AI-based platforms can predict as well as facilitate real-time monitoring of graft health[138]. AI-identification of graft detachment allows early reintervention to improve graft survival[139,140]. AI-enabled analysis of endothelial cell counts and morphology using advanced imaging systems could potentially replace traditional devices such as in-vivo confocal microscopy and provide early warnings of graft rejection or failure, allowing timely intervention[141,142]. Telemedicine integration with AI tools further enhances the feasibility of remote patient monitoring, especially for those in geographically underserved areas.

Moreover, AI has the potential to refine surgical techniques and instrumentation. AI-powered corneal endothelial cell culture therapies are gaining ground, with early evidence supporting newer cellular products for treating corneal endothelial decompensation[143]. Virtual surgical simulation powered by AI can assist in training surgeons and optimizing workflows, while robotic-assisted surgical platforms guided by AI may improve the precision of graft insertion and positioning[144]. AI-analysis of intraoperative course may predict the postoperative course and outcome of EK[145]. AI-powered patient counselling for EK may enable better compliance to therapy and better patient satisfaction in the long run[146].

Despite these promising applications, challenges remain in the integration of AI into routine clinical practice. Issues such as data standardization, algorithm validation, and regulatory approval must be addressed to ensure the safety and efficacy of these technologies. Nonetheless, the rapid pace of innovation underscores the need for continued research into AI applications in EK, paving the way for a future where technology seamlessly complements surgical expertise.

FAILURE AND REJECTION OF EK GRAFTS

As stated, the exact mechanisms of endothelial dysfunction are still being investigated, and hence the immunology involved in the process of endothelial graft failure and rejection is a matter of recent scientific interest. Graft rejection in EK is almost exclusively endothelial, as this is the only donor tissue introduced into the eye. EK procedures thus reduce disturbance to AC Associated Immune Deviation, the amount of donor antigen presenting cells, and the total amount of immunogenic tissue[147,148]. While early specific features of endothelial cells may constitute specular microscopic evidence announcing upcoming graft rejection, clinical features of frank rejection include AC cells, keratic precipitates, endothelial rejection line, and interface vascularization[21,149]. Risk factors include cessation of postoperative steroid and persons of colour[150]. When performed by skilled surgeons, the 5-year survival rates of the grafts of EK are similar or better than PK grafts. The major recipient features that impact ECD and EK survival are the indication for transplantation and previous glaucoma filtering surgery[151]. Failed endothelial grafts demonstrate specific features including thickened, edematous corneas with attenuated atrophic endothelium and varying degrees of posterior lamellar graft detachment. A fine retrocorneal fibrous membrane may be found[152]. Early failure is treated with topical corticosteroid drops and infrequently results in irreversible graft rejection requiring repeat EK.

Immunological mechanisms of graft rejection

Graft rejection in EK is primarily driven by alloimmune responses targeting donor endothelial cells. The process is mediated by a complex interplay of both innate and adaptive immune pathways[153]. Antigen-presenting cells in the recipient cornea and draining lymph nodes process donor-derived antigens and present them to T cells, leading to T cell activation. This alloimmune response involves CD4⁺ helper T cells, which orchestrate cytotoxic CD8⁺ T cell activity and the recruitment of inflammatory cells to the graft site. Inflammatory mediators such as cytokines (e.g., IL-2, IL-6, and IFN-γ) and chemokines exacerbate endothelial cell injury, leading to graft edema and failure[154]. Additionally, humoral immune responses, characterized by the production of donor-specific antibodies, contribute to endothelial cell loss through complement-mediated cytotoxicity[155,156].

Pathophysiology of endothelial cell loss

Endothelial cell loss in EK grafts is influenced by both immune-mediated and non-immune factors. In the early postoperative period, mechanical trauma during graft manipulation and insertion may initiate cell loss. Over time, immune-mediated rejection becomes a dominant cause. Chronic inflammation, endothelial apoptosis, and complement activation further exacerbate cell attrition. The balance between endothelial cell proliferation and loss determines graft survival, highlighting the importance of strategies to mitigate immune-mediated injury.

Immune-modulatory therapies for rejection prevention

Advances in immune-modulatory therapies have significantly improved graft survival rates in EK. The use of topical corticosteroids, such as prednisolone acetate 1%, remains the cornerstone of rejection prevention, with tapering regimens adjusted based on the patient's risk profile. In high-risk cases, adjunctive therapies such as topical cyclosporine A 0.05% or tacrolimus 0.03% ointment are employed to suppress T cell-mediated immune responses. Emerging therapies, including Janus kinase inhibitors and anti-complement agents like eculizumab, offer promise in modulating alloimmune responses and reducing graft rejection rates. Additionally, systemic immunosuppression with agents such as mycophenolate mofetil or low-dose oral corticosteroids may be considered in cases of recurrent rejection or in patients with autoimmune comorbidities. Recently, the role of anti-angiogenic and anti-lymphangiogenic agents is also being considered to prevent vascularization of the cornea which is a known risk factor for graft rejection[157,158].

Future directions in rejection prevention

The application of advanced imaging technologies, such as in vivo confocal microscopy, allows for real-time monitoring of ECD and early detection of subclinical rejection. Furthermore, personalized medicine approaches, including HLA matching and preoperative donor-specific antibody screening, may improve graft compatibility and reduce rejection risk. The integration of AI in predicting rejection risk and tailoring immunosuppressive regimens holds potential for optimizing outcomes in EK.

Standardized post-operative care regimens

Postoperative care following EK is critical to achieving optimal graft survival, reducing complications, and improving visual outcomes. Variability in postoperative care practices across institutions can contribute to inconsistent outcomes. This section outlines a standardized approach to postoperative care, integrating current evidence-based practices[159].

Anti-inflammatory therapy: Corticosteroids are the cornerstone for managing inflammation and preventing immune-mediated graft rejection. Suggested regimens include Prednisolone acetate 1% eye drops, 4 times daily (QID) for weeks 1-4, reduced to twice daily (BID) in months 2-3 and further to once daily (OD) in months 4-6[159]. Beyond 6 months, it recommended to transition to low-potency steroids, such as fluorometholone 0.1% or loteprednol etabonate 0.5%, to minimize long-term side effects. For high-risk cases (e.g., previous graft rejection, systemic autoimmune conditions), Dexamethasone 0.1% eye drops are preferred for potent anti-inflammatory effects in severe cases[160]. Adjunctive oral Prednisone 1 mg/kg/day may be considered during acute graft rejection episodes.

Antibiotic prophylaxi: To minimize the risk of postoperative infections, topical moxifloxacin 0.5% eye drops QID for 2 weeks can be used. Alternatives include gatifloxacin 0.3% or besifloxacin 0.6% for enhanced Gram-positive coverage. For cases with epithelial defects or persistent epithelial breakdown, fortified antibiotics such as fortified vancomycin (25 mg/mL) and tobramycin (15 mg/mL) can be utilized[160].

Adjunctive therapies: These include ocular lubricants, specifically preservative-free artificial tears (e.g., carboxymethylcellulose 0.5%-1% or hyaluronic acid 0.1%-0.2%) which are essential for mitigating dry eye symptoms and epithelial healing, either alone or alongside gel-based lubricants or ointments used at night for additional protection[160].

Antiglaucoma medications have to be added if postoperative IOP elevation occurs. Topical medications such as timolol 0.5% or brimonidine 0.15% BID or dorzolamide 2%/timolol 0.5% fixed combination can be tried for enhanced IOP control; preservative free preparations are preferred. In resistant cases, systemic carbonic anhydrase inhibitors like acetazolamide 250 mg orally BID are necessary.

Anti-Vascular Endothelial Growth Factor (anti-VEGF) therapy is indicated for patients with high-risk vascularized grafts. Adjunctive anti-VEGF injections (e.g., ranibizumab 0.5 mg or bevacizumab 1.25 mg intravitreal) can be employed pre- or postoperatively to reduce neovascularization.

Immunosuppressive Agents like Tacrolimus 0.03% eye drops can be added to standard corticosteroid therapy for high-risk cases. Systemic immunosuppressants, such as mycophenolate mofetil 1 g BID or oral tacrolimus 0.03 mg/kg/day, may be required in consultation with an immunologist.

Standardized follow-up protocol

Postoperative monitoring is essential to detect and address complications early. In the first week, graft attachment should be compulsorily assessed using slit-lamp biomicroscopy and anterior segment OCT (AS-OCT). During the first month, ECD (specular microscopy) and IOP should be monitored. In subsequent months (3, 6, and 12), endothelial cell loss, IOP, and graft clarity must be evaluated by repeat AS-OCT for structural analysis. Beyond the end of the first year, annual follow-ups should be undertaken to monitor long-term endothelial function and detect late complications, such as graft rejection or glaucoma.

Management of postoperative complications

Graft Detachment should be treated with early intervention with pneumatic tamponade using 20% SF6 or 12% C3F8 gas injection. Graft rejection should be treated with intensive corticosteroid therapy with prednisolone acetate 1% hourly and systemic corticosteroids (e.g., oral prednisone 1 mg/kg/day) for severe cases, considering adjunctive immunomodulatory therapy for refractory cases.

Persistent Epithelial Defects should be treated with bandage contact lenses combined with lubricants and prophylactic antibiotics, with Autologous serum eye drops (20%) reserved for cases with suboptimal response.

A standardized postoperative care protocol for EK improves outcomes by addressing the multifactorial challenges of graft survival and minimizing complications. The incorporation of detailed drug regimens, adjunctive therapies, and structured follow-up ensures comprehensive management, setting a benchmark for best practices.

COMMUNITY ASPECTS OF MODERN EK TECHNIQUES

EK carries with it the advantages of lamellar corneal surgeries. In the current scenario of a global deficiency of corneal tissue to combat avoidable corneal blindness, customized component corneal surgeries allow one donor corneoscleral button to be utilized for up to three recipients[161]. Wherever EK is performed, the structural integrity of the globe is maintained, avoiding any chances of catastrophic complications associated with open globe surgery[24]. Modern EK techniques have taken a step forward and converted the concept of corneal transplantation into a refractive surgery. Surgeons have progressed towards using thinner tissue, optimizing visual outcomes. Improvements have enabled better donor tissue formulation, usage, and attachment, and surgical modifications have enhanced the tissue utilization in difficult clinical scenarios lowering failure and rejection[151,162]. Globally, the number of EK procedures being performed has thus been reported to be increasing in the last decade[163]. Corneal edema post-cataract surgery (pseudophakic and ABK) and hereditary endothelial dystrophies remain the most common indications for which EK is performed[21,164].

Cost considerations

This can vary according to the type of procedure needed, medical facility and the patient’s needs. DMEK costs less than DSAEK. Preloaded graft reduces graft and surgical time. Expenses include those incurred for pre-, peri- and post-operative care, nursing care, anesthesia, simultaneous cataract or glaucoma surgery, surgeon time, management of complications and retreatment. In a retrospective cohort amongst 1562 patients of FECD who claimed insurance for EK, the cost was estimated to be $14000. In addition, the procedure itself also entails a loss of productivity due to short-term disability. The yearly estimated cost of a corneal transplant incurred in 2013 was $16500. A modelling study estimated an average $77000 direct medical benefit and $214000 indirect benefit of avoiding blindness, hence the benefits outweigh the costs[165,166].

Regulatory and ethical aspects of EK

EK currently relies almost entirely on deceased cornea donation[167]. Hence all regulatory aspects of organ donation apply to sourcing of corneal tissues from eye banks. Before proceeding to any surgery, the surgeon must be satisfied that the benefits of surgery outweigh the risks of surgery and their complications, and that the patient is willing for the life-long commitment to treatment and follow-up that the procedure would demand. A robust process for informed consent is required to safeguard the patient’s autonomy. This is highly dependent on the patients’ capacity to understand the explanations provided by health caregivers, and their ability to discuss the issue at hand with their families, to arrive at a decision and to communicate the outcome of their deliberations[168]. Herein lies the role of counsellors and other health professionals for detailed interaction with the potential recipients, while ophthalmologists also need to set aside extra chair-time for such patients. Caregivers and counsellors also take into account the ethical considerations of not treating bilaterally blind patients, the costs estimated as being twice as much as treating non-blind patients due to inability for social interactions, loss of productivity and earning[169].

FUTURE OF EK

Global shortage of transplantable donor corneas has restricted the treatment outcomes, hence prompting a necessity to explore unconventional therapies[8]. The modern era of molecular biology and cell culture has recently seen the advent of cultured corneal endothelial cell therapy, gene therapy and artificial corneal endothelial implants for advanced cases of corneal endothelial loss with considerably good results[21].

Human cultured endothelial cells (also termed cultivated autologous endothelial cells) have been found safe and effective for restoring normal endothelial function in cases of early pseudophakic endothelial failure with up to five years of clinical follow-up[170]. One HCEC graft can be generated from 1/8th of donor corneoscleral rim, potentially increasing tissue availability by 8-fold[171]. Significant improvement of corrected distance visual acuity can be achieved by injection of these cells into the AC, augmented by the topical application of rho-kinase inhibitors like Netarsudil and Ripasudil to promote endothelial adhesion to the area left bare by endothelial cell loss. Endothelial cell sheets can also be transplanted, wherein cultured endothelial cells are passaged upon confluency, suspended in culture medium, seeded on the desired carriers and transplanted by a surgical protocol akin to DMEK[172]. Additionally, adjunctive therapies that promote wound healing and modulate immune responses could play a pivotal role in further increasing success rates in challenging EK procedures.

Advancements in tissue engineering, including bioengineered corneal tissues, may also expand the scope of EK, particularly in eyes with severe scarring or other abnormalities. There are recent favorable results with implantation of an artificial endothelial replacement membrane (EndoArt, EyeYon Medical, Israel) several months after two or more failed DSEK procedures[173,174]. EndoArt is a 6 mm diameter posterior corneal contact lens 50 microns thick, that acts akin to a fluid barrier in the posterior cornea like a Nanothin DSEK graft. EndoArt is composed of hydrophilic acrylic material like intraocular lenses - time tested to be biocompatible and easy to implant. Currently it is expensive and not readily available, but has the potential to eventually obviate the need to source donor posterior corneal lenticules. In studies, morphological changes observed using AS-OCT and in-vivo confocal microscopy are similar to those observed after EK, with the exception of absence of hyper-reflective donor-host interface[175].

In the current era of AI, AI-based interpretation of specular endothelial photographs is being explored as a means to predict the propensity of candidate recipients to develop endothelial decompensation. Such interpretation is being applied to explore the donor and recipient characteristics which may decide the fate of EK grafts, and provide ground for the development of personalized EK in the future[176].

CONCLUSION

EK is the gold standard for treating endothelial dysfunction and there is a global trend that increasingly large numbers of EK procedures are being undertaken. By selectively replacing the dysfunctional endothelial cells while preserving the healthy corneal tissue, EK allows for better graft survival, a more stable refractive outcome and reduced risk of rejection. Modern improvements and minimally invasive nature of the procedure enhance patient recovery, making EK the preferred option for many patients requiring corneal transplantation. In special cases such as post-trauma eyes, pediatric patients, and those with prior ocular surgeries or complex anterior segment abnormalities, EK presents unique challenges. These complexities demand tailored surgical strategies, including modifications in graft handling, positioning, and postoperative management to ensure success. Attention to these details and addressing patient-specific factors can help improve outcomes in difficult cases.