In the past decade, novel lamellar keratoplasty techniques such as Deep Anterior Lamellar Keratoplasty (DALK) for anterior keratoplasty and Descemet stripping automated endothelial keratoplasty (DSAEK)/Descemet membrane endothelial keratoplasty (DMEK) for posterior keratoplasty have been developed. DALK eliminates the possibility of endothelial allograft rejection, which is the main reason for graft failure after penetrating keratoplasty (PK). Compared to PK, the risk of endothelial graft rejection is significantly reduced after DSAEK/DMEK. Thus, with modern lamellar techniques, the clinical problem of endothelial graft rejection seems to be nearly solved in the low-risk situation. However, even with lamellar grafts there are epithelial, subepithelial and stromal immune reactions in DALK and endothelial immune reactions in DSAEK/DMEK, and not all keratoplasties can be performed in a lamellar fashion. Therefore, endothelial graft rejection in PK is still highly relevant, especially in the "high-risk" setting, where the cornea's (lymph)angiogenic and immune privilege is lost due to severe inflammation and pathological neovascularization. For these eyes, currently available treatment options are still unsatisfactory. In this review, we will describe currently used keratoplasty techniques, namely PK, DALK, DSAEK, and DMEK. We will summarize their indications, provide surgical descriptions, and comment on their complications and outcomes. Furthermore, we will give an overview on corneal transplant immunology. A specific focus will be placed on endothelial graft rejection and we will report on its incidence, clinical presentation, and current/future treatment and prevention options. Finally, we will speculate how the field of keratoplasty and prevention of corneal allograft rejection will develop in the future.

The cornea and the skin are both organs that provide the outer barrier of the body. Both tissues have developed intrinsic mechanisms that protect the organism from a wide range of external threats, but at the same time also enable rapid restoration of tissue integrity and organ-specific function. The easy accessibility makes the skin an attractive model system to study tissue damage and repair. Findings from skin research have contributed to unravelling novel fundamental principles in regenerative biology and the repair of other epithelial-mesenchymal tissues, such as the cornea. Following barrier disruption, the influx of inflammatory cells, myofibroblast differentiation, extracellular matrix synthesis and scar formation present parallel repair mechanisms in cornea and skin wound healing. Yet, capillary sprouting, while pivotal in proper skin wound healing, is a process that is rather associated with pathological repair of the cornea. Understanding the parallels and differences of the cellular and molecular networks that coordinate the wound healing response in skin and cornea are likely of mutual importance for both organs with regard to the development of regenerative therapies and understanding of the disease pathologies that affect epithelial-mesenchymal interactions. Here, we review the principal events in corneal wound healing and the mechanisms to restore corneal transparency and barrier function. We also refer to skin repair mechanisms and their potential implications for regenerative processes in the cornea.

Eye drops of aganirsen, an antisense oligonucleotide preventing insulin receptor substrate-1 expression, inhibited corneal neovascularization in a previous dose-finding phase II study. We aimed to confirm these results in a phase III study and investigated a potential clinical benefit on visual acuity (VA), quality of life (QoL), and need for transplantation. Multicenter, double-masked, randomized, placebo-controlled phase III study. Analysis of 69 patients with keratitis-related progressive corneal neovascularization randomized to aganirsen (34 patients) or placebo (35 patients). Patients applied aganirsen eye drops (86 μg/day/eye) or placebo twice daily for 90 days and were followed up to day 180. The primary end point was VA. Secondary end points included area of pathologic corneal neovascularization, need for transplantation, risk of graft rejection, and QoL. Although no significant differences in VA scores between groups were observed, aganirsen significantly reduced the relative corneal neovascularization area after 90 days by 26.20% (P = 0.014). This improvement persisted after 180 days (26.67%, P = 0.012). Aganirsen tended to lower the transplantation need in the intent-to-treat (ITT) population at day 180 (P = 0.087). In patients with viral keratitis and central neovascularization, a significant reduction in transplantation need was achieved (P = 0.048). No significant differences between groups were observed in the risk of graft rejection. However, aganirsen tended to decrease this risk in patients with traumatic/viral keratitis (P = 0.162) at day 90. The QoL analyses revealed a significant improvement with aganirsen in composite and near activity subscores (P = 0.039 and 0.026, respectively) at day 90 in the per protocol population. Ocular and treatment-related treatment-emergent adverse events (TEAEs) were reported in a lower percentage with aganirsen compared with placebo. Only 3 serious TEAEs (2 with aganirsen and 1 with placebo) were considered treatment-related. This first phase III study on a topical inhibitor of corneal angiogenesis showed that aganirsen eye drops significantly inhibited corneal neovascularization in patients with keratitis. The need for transplantation was significantly reduced in patients with viral keratitis and central neovascularization. Topical application of aganirsen was safe and well tolerated.

The cornea is the clear window at the front of the eye and is the eye's main refractive medium. Its transparency is essential for vision. Corneal neovascularisation is a common clinical problem with serious consequences for vision; it can compromise corneal transparency and plays a major role in corneal graft rejection by breaching corneal immune privilege. In this review, we formulate a consensus on the unmet medical needs in the management of corneal neovascularisation and outline a framework for the clinical research that is needed to identify suitable agents to meet these needs.

Tarsoconjunctival flap advancement, or the Hughes procedure, is among the techniques of choice for reconstructing full-thickness lower eyelid defects so as to restore normal anatomy and function with the best possible cosmetic outcome. The purpose of this study is to report the outcome of a series of patients treated with a modified Hughes procedure following malignant tumor removal. This retrospective study included 45 consecutive cases of modified Hughes procedures performed between January 2013 and October 2015. During Hughes flap creation an incisional plane was chosen in all cases, which left Müller’s muscle attached to the superior tarsal margin, while disinserting the levator aponeurosis. All cases were grouped according to the horizontal length of the lower lid defect to be reconstructed, as well as to the type of anterior lamella reconstruction (free graft vs. inferiorly based advancement flap). Grouped data were compared for the rate of surgical success, defined as achievement of normal lid function and satisfactory cosmesis without needing further surgical interventions, and for the frequency of specific complications. Surgical success was achieved in 39 cases (87 %). The remaining cases required additional surgery for minor complications including lower-lid ectropion (4 %), pyogenic granuloma (4 %), or lower lid margin hypertrophy (2 %). Donor-site complications were not detected apart from one case of mild entropion with focal trichiasis. No case of premature flap rupture was seen. Neither the horizontal length of the lower lid defect (p = 0.489), nor the type of anterior lamella reconstruction (p = 0.349) significantly affected the surgical success. Particularly, there was no increased onset of lower-lid ectropion among patients receiving an advancement flap. The modified Hughes procedure remains a well-suited technique for reconstructing lower eyelid defects involving up to 100 % of the horizontal lid length. Leaving Müller’s muscle attached to the Hughes flap might prevent premature flap dehiscence without increasing the frequency of upper lid retractions in turn. Whether using a free skin graft or a skin-muscle advancement flap for anterior lamella reconstruction, seems to be insignificant for the functional-aesthetical outcome.