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To introduce a practical method of subretinal injection in mice and evaluate injection-induced retinal detachment (RD) and damage using a dynamic imaging system, electrophysiology, and histology. After full dilation of a 2-month-old C57BL/6J mouse pupil, the cornea near the limbus was punctured with a 30 ½-gague disposable beveled needle. A 33 ½-gauge blunt needle was inserted through the corneal perforation into the anterior chamber, avoiding the lens before going deeper into the vitreous cavity, and penetrating the inner retina to reach the subretinal space. The mice were divided into four groups: in group 1, about 80-100% of the retina was filled with subretinally injected solution; in group 2, approximately 50-70% of the retina was filled with injected solution; in group 3, the procedures were stopped before solution injection; and non-injected eyes were used as the negative control in group 4. An optical coherence tomography (OCT) imaging system was used to monitor retinal reattachment during the first three days following the injections. Histological and functional changes were examined by light microscopy and electroretinography (ERG) at five weeks post-injection. After a short-term training, a 70% success rate with 50% or more coverage (i.e., retinal blebs occupied 50% or more retinal area and filled with the injected solution) with minimal injection-related damages can be achieved. Bleb formation was associated with retinal detachment (RD) between the neuroretina and the retinal pigment epithelium (RPE) layer. Partial RD could be observed at post-injection day 1, and by day 2 most of the retina had reattached. At 5 weeks post-injection, compared to uninjected control group 4, the b-wave amplitudes of ERG decreased 22% in group 1, 16% in group 2, and 7% in group 3; the b-wave amplitudes were statistically different between the uninjected group and the groups with either 50-70% or 80-100% coverage. The subretinal injection-induced RD reattached and became stable at five weeks post-injection, although some photoreceptor damage could still be observed in and around the injection sites, especially in 80-100% coverage group. Trans-corneal subretinal injection is effective and practical, although subretinal injection-related damages can cause some morphological and functional loss.

The development of potent antibiotic alternatives with rapid bactericidal properties is of great importance in addressing the current antibiotic crisis. One representative example is the topical delivery of predatory bacteria to treat ocular bacterial infections. However, there is a lack of suitable methods for the delivery of predatory bacteria into ocular tissue. This work introduces cryomicroneedles (cryoMN) for the ocular delivery of predatory Bdellovibrio bacteriovorus (B. bacteriovorus) bacteria. The cryoMN patches are prepared by freezing B. bacteriovorus containing a cryoprotectant medium in a microneedle template. The viability of B. bacteriovorus in cryoMNs remains above 80% as found in long‐term storage studies, and they successfully impede the growth of gram‐negative bacteria in vitro or in a rodent eye infection model. The infection is significantly relieved by nearly six times through 2.5 days of treatment without substantial effects on the cornea thickness and morphology. This approach represents the safe and efficient delivery of new class of antimicrobial armamentarium to otherwise impermeable ocular surface and opens up new avenues for the treatment of ocular surface disorders. This report introduces a cryo‐delivery platform inside which the predation ability of Bdellovibrio bacteriovorus is highly reserved to impede the development of gram‐negative infections.

To compare pain during pars plana vitrectomy (PPV) following topical lidocaine jelly and sub-Tenon anesthesia versus peribulbar anesthesia. Fifty-four patients were enrolled in the study (26 in Group ST and 28 in Group PB). Baseline characteristics, including age, gender, and presence of comorbidities, were similar in both groups. The surgery performed was PPV alone in 10 and 14 patients in the ST and PB groups, respectively, and combined phacoemulsification and PPV in 16 and 14 patients in the ST and PB groups, respectively (p = 0.39, Pearson). Surgery duration (mean ± SD minutes) was similar in the two groups (62 ± 12 for ST and 70 ± 20 for PB, p = 0.09, t-Test). No patients needed supplemental topical or intravenous anesthesia during surgery. No sight- or life-threatening complication was observed in either group. VAS score was significantly lower in the ST compared to the PB group (median (interquartile range) was 1 (2.25-0) in the ST group compared to 11.5 (29.75-5) in the PB group, p< 0.0001, Wilcoxon). In this study of patients who underwent PPV for MH or ERM, topical followed by sub-Tenon anesthesia was more effective in controlling pain during the whole vitrectomy procedure than peribulbar anesthesia. Compared to peribulbar anesthesia which is administered with a sharp needle, sub-Tenon anesthesia administered with a blunt cannula may be associated with a reduced risk of such adverse events as globe perforation, retrobulbar hemorrhage, and inadvertent injection of anesthesia into the optic nerve sheath.

Purpose To assess the efficacy and safety of periocular injections of methotrexate versus triamcinolone in the management of active thyroid-associated orbitopathy. Study design Prospective, double-masked, randomized clinical trial. Methods Participants with bilateral active, moderate-to-severe thyroid-associated orbitopathy were randomly assigned to receive three periocular injections of 7.5 mg methotrexate in one orbit and three periocular injections of 20 mg triamcinolone in the contralateral orbit. Results Among the enrolled 25 patients, 18 patients completed the study. A statistically significant reduction of the mean clinical activity score was detected in both arms (from 5.2 ± 0.89 at baseline to 0.9 ± 1.7 at study endpoint, p-value < 0.001 in the methotrexate arm, and from 5.1 ± 0.9 at baseline to 1 ± 1.7 at study endpoint, p-value < 0.001 in the triamcinolone arm), mean proptosis also decreased in both arms (from 25.2 ± 3.4 mm at baseline to 23.8 ± 3.7 mm at study endpoint, p-value = 0.01 in the methotrexate arm, and from 24.2 ± 3.06 mm at baseline to 23.2 ± 3.3 mm at study endpoint, p-value = 0.049 in the triamcinolone arm). Lid aperture and soft tissue signs improved significantly in both arms in comparison to baseline. A statistically significant reduction in the intraocular pressure was observed in the methotrexate arm but not in the triamcinolone arm. 88.9% of patients in both arms were overall responders at 6 months. There was no significant difference in mean CAS, proptosis, lid aperture or rate of responders between the two arms at any visit. Both drugs were found to be safe with minimal local and systemic complications. Conclusion Periocular injections of methotrexate represent an effective and safe alternative option for the management of active, moderate-to-severe thyroid-associated orbitopathy. Although no serious complications occurred during the 6-month follow-up, the possibility of late complications such as orbital fat atrophy cannot be ruled out.

One of the most challenging efforts in drug delivery is the targeting of the eye. The eye structure and barriers render this organ poorly permeable to drugs. Quite recently the entrance of nanoscience in ocular drug delivery has improved the penetration and half-life of drugs, especially in the anterior eye chamber, while targeting the posterior chamber is still an open issue. The retina and the retinal pigment epithelium/choroid tissues, located in the posterior eye chamber, are responsible for the majority of blindness both in childhood and adulthood. In the present study, we used magnetic nanoparticles (MNPs) as a nanotool for ocular drug delivery that is capable of specific localization in the retinal pigmented epithelium (RPE) layer. We demonstrate that, following intraocular injection in Xenopus embryos, MNPs localize specifically in RPE where they are retained for several days. The specificity of the localization did not depend on particle size and surface properties of the MNPs used in this work. Moreover, through similar experiments in zebrafish, we demonstrated that the targeting of RPE by the nanoparticles is not specific for the Xenopus species.

IntroductionBecause of the great potential of vascular endothelial growth factor inhibitors (anti-VEGF) for retinal exudative diseases, an increased number of patients receives this treatment. However, during this treatment, patients are subjected to frequent invasive intravitreal injections, and the effects on reversing the process of vision loss are uncertain, which may have negative consequences for patients’ mental health. One in three patients experience at least mild symptoms of depression/anxiety. To support patients in dealing with these symptoms, an e-mental health intervention (called E-PsEYE) has been developed. E-PsEYE is based on cognitive–behavioural therapy (CBT) and contains nine modules. A stepped-care model with three steps will be used to deliver the intervention: (1) providing information and psychoeducation, (2) when symptoms of depression/anxiety persist, guided CBT is offered and supported by social workers from low vision rehabilitation services and (3) when symptoms still persist, patients are referred to their general practitioner.Methods and analysisAn economic evaluation from a healthcare and societal perspective will be conducted alongside a multicentre randomised controlled trial in two parallel groups to evaluate whether E-PsEYE is cost-effective in comparison with usual care. Participants (n=174) will be 50 years or older, have retinal exudative diseases, receive anti-VEGF treatment and have mild symptoms of depression/anxiety (assessed prior to randomisation). Main outcome measures are: depression (Patient Health Questionnaire-9), anxiety (Hospital Anxiety and Depression Scale-Anxiety) and quality-adjusted life-years (determined with the Health Utility Index-3 and the EuroQol-5 dimensions). Five measurements take place: at baseline and after 3, 6, 9 and 12 months.Ethics and disseminationThe study has been approved by the Medical Ethics Committee of the VU University Medical Centre Amsterdam. It will provide new and essential information on the cost-effectiveness of an innovative intervention for a vulnerable population. Outcomes will be disseminated through peer-reviewed publications and conference presentations.Trial registrationhttp://www.trialregister.nl, identifier: NTR6337.

Retinal degenerations are the leading causes of irreversible visual loss worldwide. Many pathologies included under this umbrella involve progressive degeneration and ultimate loss of the photoreceptor cells, with age-related macular degeneration and inherited and ischemic retinal diseases the most relevant. These diseases greatly impact patients' daily lives, with accompanying marked social and economic consequences. However, the currently available treatments only delay the onset or slow progression of visual impairment, and there are no cures for these photoreceptor diseases. Therefore, new therapeutic strategies are being investigated, such as gene therapy, optogenetics, cell replacement, or cell-based neuroprotection. Specifically, stem cells can secrete neurotrophic, immunomodulatory, and anti-angiogenic factors that potentially protect and preserve retinal cells from neurodegeneration. Further, neuroprotection can be used in different types of retinal degenerative diseases and at different disease stages, unlike other potential therapies. This review summarizes stem cell-based paracrine neuroprotective strategies for photoreceptor degeneration, which are under study in clinical trials, and the latest preclinical studies. Effective retinal neuroprotection could be the next frontier in photoreceptor diseases, and the development of novel neuroprotective strategies will address the unmet therapeutic needs.

A study assessed the use of gene editing to treat CEP290 -associated inherited retinal degeneration, a disease that causes severe early-onset vision loss in childhood, and showed safety and early evidence of efficacy.

Objective The objective of this study was to evaluate the safety and intraocular pressure (IOP)-lowering effects over 24 months of biodegradable bimatoprost sustained-release implant (Bimatoprost SR) administration versus topical bimatoprost 0.03% in patients with open-angle glaucoma (OAG). Methods This was a phase I/II, prospective, 24-month, dose-ranging, paired-eye controlled clinical trial. At baseline following washout, adult patients with OAG ( N  = 75) received Bimatoprost SR (6, 10, 15, or 20 µg) intracamerally in the study eye; the fellow eye received topical bimatoprost 0.03% once daily. Rescue topical IOP-lowering medication or single repeat administration with implant was permitted. The primary endpoint was IOP change from baseline. Safety measures included adverse events (AEs). Results At month 24, mean IOP reduction from baseline was 7.5, 7.3, 7.3, and 8.9 mmHg in eyes treated with Bimatoprost SR 6, 10, 15, and 20 µg, respectively, versus 8.2 mmHg in pooled fellow eyes; 68, 40, and 28% of pooled study eyes had not been rescued/retreated at months 6, 12, and 24, respectively. AEs in study eyes that occurred ≤ 2 days post-procedure typically were transient. After 2 days post-procedure, overall AE incidence was similar between study and fellow eyes, with some events typically associated with topical prostaglandin analogs having lower incidence in study eyes. Conclusions Bimatoprost SR showed favorable efficacy and safety profiles up to 24 months, with all evaluated dose strengths demonstrating overall IOP-reducing effects comparable to those of topical bimatoprost. Targeted and sustained delivery of bimatoprost resulted in protracted IOP lowering, suggesting that Bimatoprost SR may represent a transformational new approach to glaucoma therapy. Clinicaltrials.gov identifier: NCT01157364

Safety and efficacy have been shown in a phase 1 dose-escalation study involving a unilateral subretinal injection of a recombinant adeno-associated virus (AAV) vector containing the RPE65 gene (AAV2-hRPE65v2) in individuals with inherited retinal dystrophy caused by RPE65 mutations. This finding, along with the bilateral nature of the disease and intended use in treatment, prompted us to determine the safety of administration of AAV2-hRPE65v2 to the contralateral eye in patients enrolled in the phase 1 study. In this follow-on phase 1 trial, one dose of AAV2-hRPE65v2 (1·5 × 1011 vector genomes) in a total volume of 300 μL was subretinally injected into the contralateral, previously uninjected, eyes of 11 children and adults (aged 11–46 years at second administration) with inherited retinal dystrophy caused by RPE65 mutations, 1·71–4·58 years after the initial subretinal injection. We assessed safety, immune response, retinal and visual function, functional vision, and activation of the visual cortex from baseline until 3 year follow-up, with observations ongoing. This study is registered with ClinicalTrials.gov, number NCT01208389. No adverse events related to the AAV were reported, and those related to the procedure were mostly mild (dellen formation in three patients and cataracts in two). One patient developed bacterial endophthalmitis and was excluded from analyses. We noted improvements in efficacy outcomes in most patients without significant immunogenicity. Compared with baseline, pooled analysis of ten participants showed improvements in mean mobility and full-field light sensitivity in the injected eye by day 30 that persisted to year 3 (mobility p=0·0003, white light full-field sensitivity p<0·0001), but no significant change was seen in the previously injected eyes over the same time period (mobility p=0·7398, white light full-field sensitivity p=0·6709). Changes in visual acuity from baseline to year 3 were not significant in pooled analysis in the second eyes or the previously injected eyes (p>0·49 for all time-points compared with baseline). To our knowledge, AAV2-hRPE65v2 is the first successful gene therapy administered to the contralateral eye. The results highlight the use of several outcome measures and help to delineate the variables that contribute to maximal benefit from gene augmentation therapy in this disease. Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia, Spark Therapeutics, US National Institutes of Health, Foundation Fighting Blindness, Institute for Translational Medicine and Therapeutics, Research to Prevent Blindness, Center for Advanced Retinal and Ocular Therapeutics, Mackall Foundation Trust, F M Kirby Foundation, and The Research Foundation—Flanders.