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Corneal transplantation or keratoplasty has developed rapidly in the past 10 years. Penetrating keratoplasty, a procedure consisting of full-thickness replacement of the cornea, has been the dominant procedure for more than half a century, and successfully caters to most causes of corneal blindness. The adoption by specialist surgeons of newer forms of lamellar transplantation surgery, which selectively replace only diseased layers of the cornea, has been a fundamental change in recent years. Deep anterior lamellar keratoplasty is replacing penetrating keratoplasty for disorders affecting the corneal stromal layers, while eliminating the risk of endothelial rejection. Endothelial keratoplasty, which selectively replaces the corneal endothelium in patients with endothelial disease, has resulted in more rapid and predictable visual outcomes. Other emerging therapies are ocular surface reconstruction and artificial cornea (keratoprosthesis) surgery, which have become more widely available because of rapid advances in these techniques. Collectively, these advances have resulted in improved outcomes, and have expanded the number of cases of corneal blindness, which can now be treated successfully. Femtosecond-laser-assisted surgery, bioengineered corneas, and medical treatment for endothelial disease are also likely to play a part in the future.

Consistent expansion of human corneal endothelial cells (hCECs) is critical in the development of tissue engineered endothelial constructs. However, a wide range of complex culture media, developed from different basal media have been reported in the propagation of hCECs, some with more success than others. These results are further confounded by donor-to-donor variability. The aim of this study is to evaluate four culture media in the isolation and propagation of hCECs isolated from a series of paired donor corneas in order to negate donor variability. Isolated primary hCECs were cultured in four previously published medium coded in this study as: M1-DMEM; M2-OptiMEM-I; M3-DMEM/F12, & M4-Ham's F12/M199. Primary hCECs established in these conditions were expanded for two passages and analyzed for (1) their propensity to adhere and proliferate; (2) their expression of characteristic corneal endothelium markers: Na+K+/ATPase and ZO-1; and (3) their cellular morphology throughout the study. We found that hCECs isolated in all four media showed rapid attachment when cultured on FNC-coated dishes. However, hCECs established in the four media exhibited different proliferation profiles with striking morphological differences. Corneal endothelial cells cultured in M1 and M3 could not be propagated beyond the first and second passage respectively. The hCECs cultured in M2 and M4 were significantly more proliferative and expressed markers characteristics of human corneal endothelium: Na+K+/ATPase and ZO-1. However, the unique morphological characteristics of cultivated hCECs were not maintained in either M2 or M4 beyond the third passage.The proliferative capacity and morphology of hCECs are vastly affected by the four culture media. For the development of tissue engineered graft materials using cultured hCECs derived from the isolation methodology described in this study, we propose the use of proliferative media M2 or M4 up to the third passage, or before the cultured hCECs lose their unique cellular morphology.

Congenital hereditary endothelial dystrophy (CHED) is a heritable, bilateral corneal dystrophy characterized by corneal opacification and nystagmus. We describe seven different mutations in the SLC4A11 gene in ten families with autosomal recessive CHED. Mutations in SLC4A11 , which encodes a membrane-bound sodium-borate cotransporter, cause loss of function of the protein either by blocking its membrane targeting or nonsense-mediated decay.

The global shortage of donor corneas has garnered extensive interest in the development of graft alternatives suitable for endothelial keratoplasty using cultivated primary human corneal endothelial cells (CECs). We have recently described a dual media approach for the propagation of human CECs. In this work, we characterize the effects of a Rho-kinase inhibitor Y-27632 on the cultivation of CECs propagated using the dual media culture system. Seventy donor corneas deemed unsuitable for transplantation were procured for this study. We assessed the use of Y-27632 for its effect at each stage of the cell culture process, specifically for cell attachment, cell proliferation and during both regular passaging and cryopreservation. Lastly, comparison of donor-matched CEC-cultures expanded with or without Y-27632 was also performed. Our results showed that Y-27632 significantly improved the attachment and proliferation of primary CECs. A non-significant pro-survival effect was detected during regular cellular passage when CECs were pre-treated with Y-27632, an effect that became more evident during cryopreservation. Our study showed that the inclusion of Y-27632 was beneficial for the propagation of primary CECs expanded via the dual media approach and was able to increase overall cell yield by between 1.96 to 3.36 fold.

LASIK (laser-assisted in situ keratomileusis) is a common laser refractive procedure for myopia and astigmatism, involving permanent removal of anterior corneal stromal tissue by excimer ablation beneath a hinged flap. Correction of refractive error is achieved by the resulting change in the curvature of the cornea and is limited by central corneal thickness, as a thin residual stromal bed may result in biomechanical instability of the cornea. A recently developed alternative to LASIK called Refractive Lenticule Extraction (ReLEx) utilizes solely a femtosecond laser (FSL) to incise an intrastromal refractive lenticule (RL), which results in reshaping the corneal curvature and correcting the myopia and/or astigmatism. As the RL is extracted intact in the ReLEx, we hypothesized that it could be cryopreserved and re-implanted at a later date to restore corneal stromal volume, in the event of keratectasia, making ReLEx a potentially reversible procedure, unlike LASIK. In this study, we re-implanted cryopreserved RLs in a non-human primate model of ReLEx. Mild intrastromal haze, noted during the first 2 weeks after re-implantation, subsided after 8 weeks. Refractive parameters including corneal thickness, anterior curvature and refractive error indices were restored to near pre-operative values after the re-implantation. Immunohistochemistry revealed no myofibroblast formation or abnormal collagen type I expression after 8 weeks, and a significant attenuation of fibronectin and tenascin expression from week 8 to 16 after re-implantation. In addition, keratocyte re-population could be found along the implanted RL interfaces. Our findings suggest that RL cryopreservation and re-implantation after ReLEx appears feasible, suggesting the possibility of potential reversibility of the procedure, and possible future uses of RLs in treating other corneal disorders and refractive errors.

Hyperopia is a common refractive error, apparent in 25% of Europeans. Treatments include spectacles, contact lenses, laser interventions and surgery including implantable contact lenses and lens extraction. Laser treatment offers an expedient and reliable means of correcting ametropia. LASIK is well-established however SMILE (small-incision lenticule extraction) or lenticule implantation (derived from myopic laser-correction) are newer options. In this study we compared the outcomes of hyperopic LASIK, SMILE and lenticule re-implantation in a primate model at +2D/+4D treatment. While re-implantation showed the greatest regression, broadly comparable refractive results were seen at 3-months with SMILE and LASIK (<1.4D of intended), but a greater tendency to regression in +2D lenticule reimplantation. Central corneal thickness showed greater variation at +2D treatment, but central thickening during lenticule reimplantation at +4D treatment was seen (-17± 27μm LASIK, -45 ± 18μm SMILE and 28 ± 17μm Re-implantation; p <0.01) with expected paracentral thinning following SMILE. Although in vivo confocal microscopy appeared to show higher reflectivity in all +4D treatment groups, there were minimal and inconsistent changes in inflammatory responses between modalities. SMILE and lenticule re-implantation may represent a safe and viable method for treating hyperopia, but further optimization for lower hyperopic treatments is warranted.

In ophthalmology, the designation of trachoma, onchocerciasis and leprosy as neglected tropical diseases (NTDs) has sustained efforts to combat these blinding conditions worldwide. Over the past 50 years, NTD designations have enabled the joining of political, social and economic forces to promote research and interventions for diseases that overwhelmingly affect the 3 billion people who subsist on less than 2 United States dollars (US$) a day. The global public health landscape is still dominated by focus on human immunodeficiency virus (HIV), tuberculosis and malaria. However, NTDs are now increasingly recognized as important causes of morbidity and mortality in low-income settings, perpetuating stigma and social isolation, with many NTDs leading to disfiguring complications. In international public health diplomacy, formal disease recognition is essential. The pursuit of this recognition drives proposals from World Health Organization’s (WHO’s) Member States to include additional diseases in the list of NTDs. The intention is to strengthen the development of partnerships, epidemiological frameworks and commitment of resources to achieve the aims set by the sustainable development goals

Presbyopia remains a major visual impairment for patients, who have previously undergone laser refractive correction and enjoyed unaided distance vision prior to the onset of presbyopia. Corneal stromal volume restoration through small incision lenticule extraction (SMILE) lenticule re-implantation presents an opportunity for restoring the patients' non-dominant eye to previous low myopia to achieve a monovision. In this study, we investigated the feasibility of performing LASIK after lenticule re-implantation as a method to create presbyopic monovision. A -6.00D SMILE correction was performed in 9 rabbit eyes. The lenticules were cryopreserved for 14 days and re-implanted. Five weeks later, 3 of these eyes underwent LASIK for -5.00D correction (RL group); 3 underwent LASIK flap creation, which was not lifted (RN); and no further procedures were performed on the remaining 3 eyes. These groups were compared with 3 eyes that underwent standard LASIK for a -5.00D correction (LO); 3 that underwent creation of non-lifted flap (LN); and 3 non-operated eyes. Rabbits were euthanized 1 day post-surgery. Tissue responses were analyzed by immunohistochemistry, slit lamp and in vivo confocal microscopy (IVCM). Intrastromal irregularities and elevated reflectivity levels of the excimer-ablated plane were observed on slit lamp and IVCM, respectively in the RL group. The results were comparable (P = 0.310) to IVCM findings in the LO group. RL and LO groups showed similar fibronectin expression levels, number of CD11b-positive cells (P = 0.304) and apoptotic cells (P = 0.198). There was no difference between the RN and LN groups in reflectivity levels (P = 0.627), fibronectin expression levels, CD11b-positive cells (P = 0.135) and apoptotic cells (P = 0.128). LASIK can be performed following lenticule re-implantation to create presbyopic monovision. The tissue responses elicited after performing LASIK on corneas that have undergone SMILE and subsequent lenticule re-implantation are similar to primary procedure.

With any refractive correction, including Small Incision Lenticule Extraction (SMILE), there may be a residual refractive error that requires a retreatment. Here, we investigated the tissue responses following various retreatment procedures in a rabbit model of SMILE. All rabbits underwent a -6.00D correction with SMILE. Two weeks later, they underwent -1.00D enhancement by: (i) VisuMax Circle, followed by excimer ablation (S+C); (ii) secondary SMILE anterior to the primary procedure (S+SE); or (iii) surface ablation (S+P), and were examined for 28 days. S+P induced corneal edema and haze, and more CD11b- (23±6 cells) and TUNEL-positive (36±4 cells) cells in the central stromal superficial layers early post-operatively (p<0.001 compared to other procedures). The corneas appeared normal on day 28 after S+P, but had a lower number of keratocytes near the laser ablated plane compared to other procedures. S+SE and S+C did not induce corneal haze and resulted similar level of fibronectin. However, S+C resulted in more inflammatory (10±2 cells; p = 0.001) and apoptotic cells (25±2 cells; p<0.001) compared to S+SE (7±1 inflammatory cells and 21±3 apoptotic cells) early post-operatively. In conclusion, each SMILE retreatment method resulted in unique tissue responses. S+SE offers advantages, such as minimal inflammation and cell death, as well as maintaining a 'flap-less' surgery, over other procedures. However, depending on the degree of enhancement, the lenticule may become too thin to be extracted and the procedure becomes more difficult to perform than S+C and S+P. S+P can maintain corneal integrity by avoiding flap creation and is technically more simple to perform than the others, but the surgery needs to be supplemented with mitomycin-C in order to reduce inflammation and modulate better wound healing.

To compare four different Circle patterns for flap creation after small incision lenticule extraction (SMILE). SMILE was performed on six rabbits. Twenty-eight days after the initial procedure, corneal flaps were created using Circle patterns. Rabbits were divided into four groups (patterns A, B, C, and D). Pattern A creates a circular side cut to meet the cap cut within the clearance zone (outside of the optical zone). Patterns B, C, and D create a lamellar ring posterior, anterior, and at the same depth, respectively, to the cap to meet the cap cut in the clearance zone with the help of a junction cut. Difficulty of flap lift was graded from 1 (easiest) to 5 (most difficult). The bed quality was assessed by scanning electron microscopy. Flaps created by patterns A and D were the easiest to lift (grade 2). The resulting flap bed was smooth and undisrupted. However, pattern A resulted in a reduced re-treatment area. Flaps created by pattern B were the most difficult to lift (grade 4). The stromal dissection was difficult in an attempt to ascertain the original optical zone from the lamellar ring, placed posterior. Flaps produced by pattern C were easy to lift, with minor intrastromal resistance experienced during the lifting process (grade 3). The transition between the lamellar ring and cap cut was hardly discernible in pattern C-treated corneas. Pattern D, a lamellar ring adjacent to the cap cut, was the most optimal to be used for flap creation in cases of SMILE re-treatment.