OBJECTIVE: Corneal collagen crosslinking (CXL) is the primary treatment for progressive keratoconus which has a significant impact on vision and quality of life. Our study aimed to compare the efficacy and safety of epithelium-on versus epithelium-off CXL to treat keratoconus.
METHODS: We searched PubMed, Medline, Embase, Web of Science, and Scopus databases. We included studies that compared standard epithelium-off with epithelium-on CXL. The primary outcome measures were changes in corrected distance visual acuity (CDVA) and maximum keratometry (Kmax), and the secondary outcomes were uncorrected distance visual acuity (UDVA), central corneal thickness (CCT), and adverse events. A meta-analysis was performed on the primary and secondary outcomes based on the weighted mean differences between baseline to 12-month follow-up.
RESULTS: The search retrieved 887 publications with 27 included in the systematic review. A total of 1622 eyes (1399 patients; age 25.51 ± 4.02 years) were included in comparisons of epithelium-off to epithelium-on CXL in keratoconus. Epithelium-off CXL treated 800 eyes and epithelium-on CXL for 822 eyes. At 12-month follow-up, CDVA and Kmax showed no significant difference between the epithelium-off and epithelium-on CXL. The secondary outcomes showed that UDVA was better in epithelium-off CXL (- 0.11D, 95% CI - 0.12, - 0.1; p < 0.001) and there was more thinning in CCT in epithelium-off CXL (- 3.23 μm, 95% CI - 4.64, - 1.81; p <0.001).
CONCLUSIONS: Epithelium-off and epithelium-on CXL were both effective to treat progressive keratoconus. Further research is needed to compare the long-term outcomes and safety of both CXL protocols for adaptation into clinical practice.

Diabetes mellitus is a global public health problem with both macrovascular and microvascular complications, such as diabetic corneal neuropathy (DCN). Using in-vivo confocal microscopy, corneal nerve changes in DCN patients can be examined. Additionally, changes in the morphology and quantity of corneal dendritic cells (DCs) in diabetic corneas have also been observed. DCs are bone marrow-derived antigen-presenting cells that serve both immunological and non-immunological roles in human corneas. However, the role and pathogenesis of corneal DC in diabetic corneas have not been well understood. In this article, we provide a comprehensive review of both animal and clinical studies that report changes in DCs, including the DC density, maturation stages, as well as relationships between the corneal DCs, corneal nerves, and corneal epithelium, in diabetic corneas. We have also discussed the associations between the changes in corneal DCs and various clinical or imaging parameters, including age, corneal nerve status, and blood metabolic parameters. Such information would provide valuable insight into the development of diagnostic, preventive, and therapeutic strategies for DM-associated ocular surface complications.

The limbal stem cells niche (LSCN) is an optimal microenvironment that provides the limbal epithelial stem cells (LESCs) and strictly regulates their proliferation and differentiation. Disturbing the LSCN homeostasis can lead to limbal stem cell dysfunction (LSCD) and subsequent ocular surface aberrations, such as corneal stromal inflammation, persistent epithelial defects, corneal neovascularisation, lymphangiogenesis, corneal opacification, and conjunctivalization. As ocular surface disorders are considered the second main cause of blindness, it becomes crucial to explore different therapeutic strategies for restoring the functions of the LSCN. A major limitation of corneal transplantation is the current shortage of donor tissue to meet the requirements worldwide. In this context, it becomes mandatory to find an alternative regenerative medicine, such as using cultured limbal epithelial/stromal stem cells, inducing the production of corneal like cells by using other sources of stem cells, and using tissue engineering methods aiming to produce the three-dimensional (3D) printed cornea. Limbal epithelial stem cells have been considered the magic potion for eye treatment. Epithelial and stromal stem cells in the limbal niche hold the responsibility of replenishing the corneal epithelium. These stem cells are being used for transplantation to maintain corneal epithelial integrity and ultimately sustain optimal vision. In this review, we summarised the characteristics of the LSCN and their current and future roles in restoring corneal homeostasis in eyes with LSCD.

Rho kinase inhibitors (ROCKi) have attracted growing multidisciplinary interest, particularly in Ophthalmology where the question as to how they promote corneal endothelial healing remains unresolved. Concurrently, stem cell biology has rapidly progressed in unravelling drivers of stem cell (SC) proliferation and differentiation, where mechanical niche factors and the actin cytoskeleton are increasingly recognized as key players. There is mounting evidence from the study of the peripheral corneal endothelium that supports the likelihood of an internal limbal stem cell niche. The possibility that ROCKi stimulate the endothelial SC niche has not been addressed. Furthermore, there is currently a paucity of data that directly evaluates whether ROCKi promotes corneal endothelial healing by acting on this limbal SC niche located near the transition zone. Therefore, we performed a systematic review examining the effects ROCKi on the proliferation and differentiation of human somatic SC, to provide insight into its effects on various human SC populations. An appraisal of electronic searches of four databases identified 1 in vivo and 58 in vitro studies (36 evaluated proliferation while 53 examined differentiation). Types of SC studied included mesenchymal (n = 32), epithelial (n = 11), epidermal (n = 8), hematopoietic and other (n = 8). The ROCK 1/2 selective inhibitor Y-27632 was used in almost all studies (n = 58), while several studies evaluated ≥2 ROCKi (n = 4) including fasudil, H-1152, and KD025. ROCKi significantly influenced human somatic SC proliferation in 81% of studies (29/36) and SC differentiation in 94% of studies (50/53). The present systemic review highlights that ROCKi are influential in regulating human SC proliferation and differentiation, and provides evidence to support the hypothesis that ROCKi promotes corneal endothelial division and maintenance via acting on the inner limbal SC niche.

A review of miRNA (microRNA) profiling studies in keratoconus.
Literature search strategy-PubMed central database, using miRNA or microRNA and keratoconus as keywords.
Eleven experimental or clinical studies on humans regarding miRNA and keratoconus, published in English between 2009 and 2020 were retrieved.
The publications regarding the role of miRNAs in keratoconus are scarce and diverse but provide some valuable information about potential new mechanisms of keratoconus development and progression. The cornea expresses almost 300 different miRNAs, 18 of which are specific, and miR-184 is by far the most abundant, with expression restricted to central basal and suprabasal epithelial cells. Mutations in the seed region of MIR184 were proved to be rare and nonspecific in patients with isolated keratoconus. Overall, in keratoconus, a total of 29 miRNAs were upregulated, and 11 were downregulated. It appeared that miR-143-3p, miR-182-5p, and miR-92a-3p were highly expressed, while the miRNAs connected to cell-cell junction, cell division, and motor activity were downregulated. In less advanced forms, altered expression of four miRNAs-miR-151a-3p, miR-194-5p, miR-195-5p, miR-185-5p-was proved in the cone epithelium; in contrast, in advanced keratoconus, the expression of miR-151a-3p and miR-194-5p remained altered, changes in the expression of miR-195 and miR-185 were not reported, and the expression of miR-138-5p, miR-146b-5p, miR-28-5p, and miR-181a-2-3p was also altered in the corneal epithelium. Keratoconus is a dynamic process of corneal stromal thinning that might result from a dynamic miRNA expression in the corneal epithelium exposed to environmental and behavioral factors causing repetitive traumas. Further experimental studies are needed to prove this hypothesis.

UNASSIGNED: Thygeson superficial punctate keratitis (TSPK) is clinically characterized by exacerbations and remissions of gray-white opacities within the corneal epithelium, most often bilateral but may be asymmetric. Symptoms typically include photophobia, tearing, blurring, and eye irritation. Although disease progression and prognosis are well described, the exact cause is unknown. Hypotheses exist implicating virus-mediated immunity as the cause of TSPK following cases of viral keratitis; however, several polymerase chain reaction studies refute the infectious process concurrently with symptomatic TSPK. This is further supported by the consistent lack of response to antiviral and antibacterial treatment. A subset of dendritic cells known as Langerhans cells (LC) found within the corneal epithelium has been positively correlated with exacerbations of TSPK. Langerhans cells proliferate to protect and mitigate the cornea\'s inflammatory response, but the inflammatory triggers and relapses associated with TSPK are not well understood. Several topical drugs exist to treat inflammation related to TSPK; however, drug delivery is a major barrier to treatment because of the tear film and epithelial barrier. Drug-eluting contact lenses that target intermediates of inflammation could serve as a more effective treatment modality because of the increased bioavailability of the drugs. This review is an in-depth survey of the literature regarding the relationship between the origin and pathophysiology of LC and TSPK at the immunologic level. We also discuss potential pharmacotherapeutic interventions for TSPK prevention and treatment.

UNASSIGNED: The Rho kinase inhibitor netarsudil is a recently approved therapeutic option for the management of increased intraocular pressure in the United States. Although phase 3 clinical trials noted corneal changes related to the medication-namely, nonvisually-significant corneal verticillata-descriptions of a unique form of cystic epithelial edema began to surface as netarsudil (and its sister drug ripasudil, approved in Japan) gained widespread use. This series adds 3 new cases and reviews the current literature on this unique side effect.

The corneal epithelium contains a population of resident immune cells commonly referred to as dendritic cells (DCs), or Langerhans cells. A unique advantage of the transparent cornea being situated at the surface of the eye is that these cells can be readily visualised using in vivo confocal microscopy. Over the past decade, interest in the involvement of corneal DCs in a range of ocular and systemic diseases has surged. For most studies, the number of corneal DCs has been the main outcome of interest. However, more recently attention has shifted towards understanding how DC morphology may provide insights into the inflammatory status of the cornea, and in some cases, the health of the peripheral nervous system. In this review, we provide examples of recent methodologies that have been used to classify and measure corneal DC morphology and discuss how this relates to local and systemic inflammatory conditions in humans and rodents.

OBJECTIVE: To conduct a systematic review of clinical research on the use of regenerative medicine for the cornea in human patients.
METHODS: A systematic literature search of MEDLINE and the Cochrane Library was performed in May 2020.
RESULTS: Forty-two articles were identified. Thirty-eight of those articles focused on the treatment for limbal stem cell deficiency (LSCD), of which 17 articles involved autologous cultured limbal epithelial cell sheet transplantation (CLET), 13 involved allogeneic CLET, and 14 involved autologous cultured oral mucosal epithelial cell sheet transplantation (COMET). For autologous CLET, the median ocular surface reconstruction rate, visual recovery rate, incidence of immunologic rejection, infectious keratitis, and ocular hypertension/glaucoma were 74.1%, 54.5%, 0%, 4.6%, and 6.3%, respectively. For allogeneic CLET, they were 71.4%, 71.4%, 7.1%, 12.0%, and 7.1%, respectively. For autologous COMET, they were 66.7%, 66.7%, 0%, 5.3%, and 8.1%, respectively. Systemic immunosuppressants and steroid medications were predominantly used following allogeneic CLET, whereas they were not routinely used after autologous CLET. Three studies focused on the treatment of keratoconus using autologous adipose-derived adult stem cells and reported no marked adverse events. One study reported on the treatment of bullous keratopathy using allogeneic cultured corneal endothelial cells. All patients achieved an endothelial cell density of >500 cells, and the corrected distance visual acuity improved in 82% of the treated eyes.
CONCLUSIONS: The results show that regenerative medicine for the cornea demonstrated a satisfactory efficacy and safety. Through translational research, we are expecting to establish a new treatment for waiting patients.

This systematic review (SR) assessed the efficacy, safety and cost-effectiveness of cell-based therapy to manage limbal stem cell deficiency (LSCD), a sight-threatening orphan condition most frequently associated with severe chemical or thermal burns. LSCD has historically been treated by transplanting limbal tissue. In 1997, a new treatment, cultured limbal epithelial autografts, was described for unilateral LSCD. In cases of bilateral disease cultured autologous oral mucosa stem cells have been used. The relative efficacy of different cultured tissue procedures is unknown.
A protocol was registered with PROSPERO (CRD42017081117). Searches were conducted in 14 databases and 6 conference websites. Two reviewers independently selected studies, conducted data extraction and assessed risk of bias. One reviewer extracted individual patient data (IPD); a second checked extracted data. Data were assessed to determine the feasibility of statistical analysis, with Bayesian synthesis used to estimate improvement achieved by different treatments.
Fifty-two studies were eligible for inclusion (1113 eyes); 41 studies (716 eyes) reported IPD. No evidence was identified on cost-effectiveness. This SR was unable to confirm that any of the types of ex vivo cultured stem cell transplants identified for LSCD treatment were statistically superior when assessed against the outcomes of interest.
We believe this SR is the first to include IPD analysis of LSCD data. There is no evidence for the superiority of any method of limbal stem cell transplant. Confirmation of the safety and efficacy of this treatment modality is challenging due to heterogeneity within and between the studies identified. Therefore, recommendations for future research are proposed.