Ocular injuries caused by chemical and thermal burns are often unmanageable and frequently result in disfigurement, corneal haze/opacification, and vision loss. Currently, a considerable number of surgical and pharmacological approaches are available to treat such injuries at either an acute or a chronic stage. However, these existing interventions are mainly directed at (and limited to) suppressing corneal inflammation and neovascularization while promoting re-epithelialization. Reconstruction of the ocular surface represents a suitable but last-option recourse in cases where epithelial healing is severely impaired, such as due to limbal stem cell deficiency. In this concise review, we discuss how biomechanical modulation therapy (BMT) may represent a more effective approach to promoting the regeneration of ocular tissues affected by burn injuries via restoration of the limbal stem cell niche. Specifically, the scientific basis supporting this new therapeutic modality is described, along with our growing understanding of the role that tissue biomechanics plays in stem cell fate and function. The potential impact of BMT as a future treatment option for the management of injuries affecting tissue compliance is also further discussed.

PurposeTo evaluate the effect of background brightness on the preferred retinal locus (PRL) in patients with macular disease.MethodsThe study included 27 eyes (27 patients) with macular disease. Microperimetry (MP) was performed to evaluate the PRL and retinal sensitivity (RS) at 10 cd/m2. A prototypical device was used to evaluate the PRL at 650 cd/m2. Patients were divided into two groups: central fixation (CF) and eccentric fixation (EF).ResultsThe PRLs under different brightness levels differed significantly (P < 0.001) in 15 of 27 eyes (two of 13 eyes in the CF group and 13 of 14 eyes in the EF group). The best-corrected visual acuities (BCVAs) in eyes with different PRLs were significantly worse (P = 0.019) than in eyes with one PRL, although the foveal RS did not differ significantly. In patients with BCVAs over 0.1, the PRLs differed in four of 13 eyes in the CF group and in three of four eyes in the EF group (P > 0.05); in patients with BCVAs of 0.1 or lower, the PRLs differed in one of four eyes and 10 of 10 eyes, respectively (P = 0.011).ConclusionsIn patients with macular disease, PRLs can change depending on the surrounding brightness. It may be beneficial to evaluate PRLs under brighter background conditions (e.g., in ambient light) when performing visual rehabilitation for these patients.Translational RelevanceThis study provides important information for visual rehabilitation of patients with macular disease.

PurposeThe purpose of this study was to summarize and evaluate artificial intelligence (AI) algorithms used in geographic atrophy (GA) diagnostic processes (e.g. isolating lesions or disease progression).MethodsThe search strategy and selection of publications were both conducted in accordance with the Preferred of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed and Web of Science were used to extract literary data. The algorithms were summarized by objective, performance, and scope of coverage of GA diagnosis (e.g. lesion automation and GA progression).ResultsTwenty-seven studies were identified for this review. A total of 18 publications focused on lesion segmentation only, 2 were designed to detect and classify GA, 2 were designed to predict future overall GA progression, 3 focused on prediction of future spatial GA progression, and 2 focused on prediction of visual function in GA. GA-related algorithms reported sensitivities from 0.47 to 0.98, specificities from 0.73 to 0.99, accuracies from 0.42 to 0.995, and Dice coefficients from 0.66 to 0.89.ConclusionsCurrent GA-AI publications have a predominant focus on lesion segmentation and a minor focus on classification and progression analysis. AI could be applied to other facets of GA diagnoses, such as understanding the role of hyperfluorescent areas in GA. Using AI for GA has several advantages, including improved diagnostic accuracy and faster processing speeds.Translational RelevanceAI can be used to quantify GA lesions and therefore allows one to impute visual function and quality-of-life. However, there is a need for the development of reliable and objective models and software to predict the rate of GA progression and to quantify improvements due to interventions.

PurposeTo observe the macular pigment (MP) appearances in eyes with macular hole (MH) and clarify the origin of the appearances. The mechanisms underlying the development of MH are discussed based on the observation of MP.MethodsThis observational case series included 33 eyes of 31 patients with MH who underwent vitrectomy. The MP optical density was measured using the two-wavelength fundus autofluorescence technique. The exact localization of MP was evaluated by comparing MP distribution images and optical coherent tomography B-scan images.ResultsMP was missing at the MH. The area of the MP defect corresponded with the area of the defect of outer plexiform layer. MP was present in the retinal flap in stage 2 MH that included glia (Müller cells) and plexiform layers and in the operculum in stage 3 MH, which mainly comprised Müller cells. Cystic spaces in the outer plexiform layer surrounding stage 3 and 4 MHs showed a honeycomb appearance on MP images. MP reappeared to form an irregularly shaped pigment plane after surgical closure of MH. The MP optical volume did not change before and after surgery. Fellow eyes with a central dip in MP distribution subsequently developed MH.ConclusionsThe characteristic appearances of MP at the MH were attributed to MP in the plexiform layers and Müller cell cones. A central dip of MP distribution might be a sign of Müller cell cone damage that proceeds with MH formation.Translational RelevanceObservation of MP was useful for understanding the mechanisms of MH formation.

PurposeThe epithelium lining the ocular surface, which includes corneal and conjunctival epithelia, expresses the prosecretory chloride channel cystic fibrosis transmembrane conductance regulator (CFTR) and the proabsorptive epithelial sodium channel (ENaC). Here, methodology was established to measure the millivolt (mV) potential differences at the ocular surface, called ocular surface potential difference (OSPD), in human subjects produced by ion transport.MethodsOSPD was measured in human subjects in which a fluid-filled measuring electrode contacted a fluid pool created by eversion of the lateral lower eyelid, with a reference electrode placed subcutaneously in the forearm. Through the use of a high-impedance voltmeter, OSPD was measured continuously over 10 to 15 minutes in response to a series of perfusate fluid exchanges.ResultsBaseline OSPD (± SEM) in six normal human subjects was –21.3 ± 3.6 mV. OSPD depolarized by 1.7 ± 0.6 mV following the addition of the ENaC inhibitor amiloride, hyperpolarized by 6.8 ± 1.5 mV with a zero chloride solution, and further hyperpolarized by 15.9 ± 1.6 mV following CFTR activation by isoproterenol. The isoproterenol-induced hyperpolarization was absent in two cystic fibrosis subjects lacking functional CFTR. OSPD measurement produced minimal epithelial injury.ConclusionsOur results establish the feasibility and safety of OSPD measurement in humans and demonstrate robust CFTR activity, albeit minimal ENaC activity, at the ocular surface. OSPD measurement may be broadly applicable to investigate fluid transport mechanisms and test drug candidates to treat ocular surface disorders.Translational RelevanceTo the best of our knowledge, this is the first measurement of the electrical potential generated by the ocular surface epithelium in human subjects, offering a new approach to study ocular surface function and health.

PurposeTo develop a practical technique for visualizing and quantifying retinal ganglion cell (RGC) axon bundles in vivo.MethodsWe applied visible-light optical coherence tomography (vis-OCT) to image the RGC axon bundles, referred to as vis-OCT fibergraphy, of healthy wild-type C57BL/6 mice. After vis-OCT imaging, retinas were flat-mounted, immunostained with anti-beta-III tubulin (Tuj1) antibody for RGC axons, and imaged with confocal microscopy. We quantitatively compared the RGC axon bundle networks imaged by in vivo vis-OCT and ex vivo confocal microscopy using semi-log Sholl analysis.ResultsSide-by-side comparison of ex vivo confocal microscopy and in vivo vis-OCT confirmed that vis-OCT fibergraphy captures true RGC axon bundle networks. The semi-log Sholl regression coefficients extracted from vis-OCT fibergrams (3.7 ± 0.8 mm–1) and confocal microscopy (3.6 ± 0.3 mm–1) images also showed good agreement with each other (n = 6).ConclusionsWe demonstrated the feasibility of using vis-OCT fibergraphy to visualize RGC axon bundles. Further applying Sholl analysis has the potential to identify biomarkers for non-invasively assessing RGC health.Translational RelevanceOur novel technique for visualizing and quantifying RGC axon bundles in vivo provides a potential measurement tool for diagnosing and tracking the progression of optic neuropathies.

PurposeTo present a fully automatic method to estimate the corneal endothelium parameters from specular microscopy images and to use it to study a one-year follow-up after ultrathin Descemet stripping automated endothelial keratoplasty.MethodsWe analyzed 383 post ultrathin Descemet stripping automated endothelial keratoplasty images from 41 eyes acquired with a Topcon SP-1P specular microscope at 1, 3, 6, and 12 months after surgery. The estimated parameters were endothelial cell density (ECD), coefficient of variation (CV), and hexagonality (HEX). Manual segmentation was performed in all images.ResultsOur method provided an estimate for ECD, CV, and HEX in 98.4% of the images, whereas Topcon's software had a success rate of 71.5% for ECD/CV and 30.5% for HEX. For the images with estimates, the percentage error in our method was 2.5% for ECD, 5.7% for CV, and 5.7% for HEX, whereas Topcon's software provided an error of 7.5% for ECD, 17.5% for CV, and 18.3% for HEX. Our method was significantly better than Topcon's (P < 0.0001) and was not statistically significantly different from the manual assessments (P > 0.05). At month 12, the subjects presented an average ECD = 1377 ± 483 [cells/mm2], CV = 26.1 ± 5.7 [%], and HEX = 58.1 ± 7.1 [%].ConclusionsThe proposed method obtains reliable and accurate estimations even in challenging specular images of pathologic corneas.Translational RelevanceCV and HEX, not currently used in the clinic owing to a lack of reliability in automatic methods, are useful biomarkers to analyze the postoperative healing process. Our accurate estimations allow now for their clinical use.

PurposeHigh circulating levels of the hormone prolactin (PRL) protect against experimental diabetic retinopathy (DR) due to the retinal accumulation of vasoinhibin, a PRL fragment that inhibits blood vessel permeability and growth. A phase 2 clinical trial is investigating a new therapy for DR based on elevating serum PRL levels with levosulpiride, a prokinetic dopamine D2 receptor blocker. Here, we tested whether levosulpiride-induced hyperprolactinemia elevates PRL and vasoinhibin in the vitreous of volunteer patients with proliferative DR (PDR) undergoing elective pars plana vitrectomy.MethodsPatients were randomized to receive placebo (lactose pill, orally TID; n = 19) or levosulpiride (25 mg orally TID; n = 18) for the 7 days before vitrectomy. Vitreous samples from untreated non-diabetic (n = 10) and PDR (n = 17) patients were also studied.ResultsLevosulpiride elevated the systemic (101 ± 13 [SEM] vs. 9.2 ± 1.3 ng/mL, P < 0.0001) and vitreous (3.2 ± 0.4 vs. 1.5 ± 0.2 ng/mL, P < 0.0001) levels of PRL, and both levels were directly correlated (r = 0.58, P < 0.0002). The vitreous from non-diabetic patients or from PDR patients treated with levosulpiride, but not from placebo-treated PDR patients, inhibited the basic fibroblast growth factor (bFGF)- and vascular endothelial growth factor (VEGF)-induced proliferation of endothelial cells in culture. Vasoinhibin-neutralizing antibodies reduced the vitreous antiangiogenic effect. Matrix metalloproteases (MMPs) in the vitreous cleaved PRL to vasoinhibin, and their activity was higher in non-diabetic than in PDR patients.ConclusionsLevosulpiride increases the levels of PRL in the vitreous of PDR patients and promotes its MMP-mediated conversion to vasoinhibin, which can inhibit angiogenesis in DR.Translational RelevanceThese findings support the potential therapeutic benefit of levosulpiride against vision loss in diabetes.

PurposeTo examine differences in sleep between myopic and non-myopic children.MethodsObjective measurements of sleep, light exposure, and physical activity were collected from 91 children, aged 10 to 15 years, for two 14-day periods approximately 6 months apart. Sleep parameters were analyzed with respect to refractive error, season, day of the week, age, and sex.ResultsMyopic children exhibited differences in sleep duration by day of the week (P < 0.001) and season (P = 0.007). Additionally, myopic children exhibited shorter sleep latency than non-myopic children (P = 0.04). For all children, wake time was later (P < 0.001) and sleep duration was longer (P = 0.03) during the cooler season compared with the warmer season. On weekends, children went to bed later (P < 0.001), woke up later (P < 0.001), and had increased sleep duration (P < 0.001) than on weekdays. Younger children exhibited earlier bedtime (P = 0.005) and wake time (P = 0.01) than older children. Time spent outdoors was positively associated with sleep duration (P = 0.03), and daily physical activity was negatively associated with wake time (P < 0.001).ConclusionsMyopic children tended to have more variable sleep duration and shorter latency than non-myopic children. Sleep patterns were influenced by season, day of the week, age, time outdoors, and activity.Translational RelevanceMyopic children tended to have more variable sleep duration and shorter latency than non-myopic children, which may reflect previously reported differences in environmental and behavioral factors between refractive error groups.

PurposeTo investigate feasibility and reliability of 3-dimensional full circumpapillary retinal nerve fiber layer (cpRNFL) analysis in children, with and without glaucoma, without the use of sedation and to recommend a protocol for hand-held optical coherence tomography use.MethodsA cohort of pediatric glaucoma patients and normal children were imaged with hand-held optical coherence tomography to assess the feasibility of obtaining full cpRNFL. Two consecutive scans were acquired in a smaller sample to investigate test–retest repeatability and interassessor reproducibility. The cpRNFL thickness was assessed in four quadrants, at several visual angles from the optic nerve center.ResultsScanning was attempted in both eyes of 90 children with pediatric glaucoma and 180 controls to investigate feasibility (mean age, 6.98 ± 4.42 years). Scanning was not possible in 68 eyes of glaucoma children mainly owing to nystagmus, unclear optical media, or high refractive errors. Where three-dimensional imaging was possible, success at obtaining full cpRNFL was 67% in children with glaucoma and 89% for controls. Seventeen children with pediatric glaucoma and 34 controls contributed to reliability analysis (mean age, 6.3 ± 3.63 years). For repeatability intraclass correlation coefficients across quadrants ranged from 0.63 to 0.82 at 4° and improved to 0.88 to 0.94 at 6°. Intraclass correlation coefficients for reproducibility were also highest at 6° (>0.97 across all quadrants).ConclusionsWe demonstrate that acquisition and measurement of cpRNFL thickness values using 3-dimensional hand-held optical coherence tomography volumes in awake children is both feasible and reliable and is optimal at 6° from optic nerve center.Translational RelevanceOur recommended protocol provides guidance on how pediatric optic nerve pathologies are managed by clinicians.