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PurposeExosomes derived from human mesenchymal stem cells (hMSCs) cultured under hypoxic conditions contain proteins and growth factors that promote angiogenesis. This study investigated the effect of intravitreal administration of these exosomes on retinal ischemia using a murine model.MethodsOxygen-induced retinopathy (OIR) was induced by exposing one-week-old male C57BL/6J mice to 5 days of 75% hyperoxic conditioning, and returning to room air. After hyperoxic conditioning, the right eye of each mouse was injected intravitreally with 1 µl saline or exosomes derived from hMSCs and compared to control mice of the same age raised in room air without OIR injected intravitreally with saline. Two weeks post-injection, fluorescein angiography (FA) and phase-variance optical coherence tomography angiography (pvOCTA) were used to assess retinal perfusion. Retinal thickness was determined by OCT. The extent of retinal neovascularization was quantitated histologically by counting vascular nuclei on the retinal surface.ResultsAmong eyes with OIR, intravitreal exosome treatment partially preserved retinal vascular flow in vivo and reduced associated retinal thinning; retinal thickness on OCT was 111.1 ± 7.4µm with saline versus 132.1 ± 11.6µm with exosome, p < 0.001. Retinal neovascularization among OIR eyes was reduced with exosome treatment when compared to saline-treated eyes (7.75 ± 3.68 versus 2.68 ± 1.35 neovascular nuclei per section, p < 0.0001). No immunogenicity or ocular/systemic adverse effect was associated with intravitreal exosome treatment.ConclusionsIntravitreal administration of exosomes derived from hMSCs was well tolerated without immunosuppression and decreased the severity of retinal ischemia in this murine model. This appealing novel non-cellular therapeutic approach warrants further exploration.

PurposeTo evaluate the accuracy and precision of different syringe designs for intravitreal injection of anti-VEGF agents.MethodsVolume output was measured from three syringe designs-1) 1.0 mL tuberculin syringe, 2) 1.0 mL syringe with low dead space plunger, and 3) 0.5 mL low-volume syringe-to deliver 50 µL of bevacizumab, ranibizumab, or aflibercept, each repeated four times by three different physicians for 108 total simulated injections. Volume output was calculated from difference in syringe weight before and after expelling the drug. Accuracy was determined by mean absolute percentage error (MAPE), and precision was measured by coefficient of variation (CV).ResultsVolume output from all three syringes was significantly different from 50 µL, with mean volumes of 58.0 ± 5.7 µL for the tuberculin syringe, 58.0 ± 4.0 µL for the low dead space syringe, and 55.5 ± 5.1 µL for the low-volume syringe (p < 0.00001 for all). The low-volume syringe was the most accurate (MAPE = 12.8 ± 7.8% vs. 17.3 ± 9.3% or 15.9 ± 8.1%), and the low dead space syringe was the most reproducible (CV = 0.068 vs. 0.091 or 0.097). There was no significant difference in volume output between different anti-VEGF agents.ConclusionsIntravitreal injections of anti-VEGF agents using a 1.0 mL tuberculin syringe demonstrate poor accuracy and precision. A lower capacity syringe may improve accuracy, while a low dead space plunger may improve precision.

Rhegmatogenous retinal detachment (RRD) requires surgical intervention for its repair. There are variable techniques used for this purpose, and they are all being continuously refined. In this review, we detail the recent innovations in surgical management of RRD and proliferative vitreoretinopathy (PVR).

The most common cause of untreatable vision loss is dysfunction of the retina. Conditions, such as age-related macular degeneration, diabetic retinopathy and glaucoma remain leading causes of untreatable blindness worldwide. Various stem cell approaches are being explored for treatment of retinal regeneration. The rationale for using bone marrow stem cells to treat retinal dysfunction is based on preclinical evidence showing that bone marrow stem cells can rescue degenerating and ischemic retina. These stem cells have primarily paracrine trophic effects although some cells can directly incorporate into damaged tissue. Since the paracrine trophic effects can have regenerative effects on multiple cells in the retina, the use of this cell therapy is not limited to a particular retinal condition. Autologous bone marrow-derived stem cells are being explored in early clinical trials as therapy for various retinal conditions. These bone marrow stem cells include mesenchymal stem cells, mononuclear cells and CD34+ cells. Autologous therapy requires no systemic immunosuppression or donor matching. Intravitreal delivery of CD34+ cells and mononuclear cells appears to be tolerated and is being explored since some of these cells can home into the damaged retina after intravitreal administration. The safety of intravitreal delivery of mesenchymal stem cells has not been well established. This review provides an update of the current evidence in support of the use of bone marrow stem cells as treatment for retinal dysfunction. The potential limitations and complications of using certain forms of bone marrow stem cells as therapy are discussed. Future directions of research include methods to optimize the therapeutic potential of these stem cells, non-cellular alternatives using extracellular vesicles, and in vivo high-resolution retinal imaging to detect cellular changes in the retina following cell therapy.

PurposeTo assess the reliability of manual choroidal thickness measurements by comparing different posterior boundary definitions of the choroidal-scleral junction on enhanced depth imaging optical coherence tomography (EDI-OCT).DesignReliability analysis.MethodsTwo graders marked the choroidal-scleral junction with segmentation software using different posterior boundaries: (1) the outer border of the choroidal vessel lumen, (2) the outer border of the choroid stroma, and (3) the inner border of the sclera, to measure the vascular choroidal thickness (VCT), stromal choroidal thickness (SCT), and total choroidal thickness (TCT), respectively. Measurements were taken at 0.5-mm intervals from 1.5 mm nasal to 1.5 mm temporal to the fovea, and averaged continuously across the central 3 mm of the macula. Intraclass correlation coefficient (ICC) and coefficient of reliability (CR) were compared to assess intergrader and intragrader reliability.ResultsChoroidal thickness measurements varied significantly with different posterior boundaries (P < .001 for all). Intergrader ICCs were greater for SCT (0.959-0.980) than for TCT (0.928-0.963) and VCT (0.750-0.869), even in eyes where choroidal-scleral junction visibility was

PurposeIntravitreal murine lineage-negative bone marrow (BM) hematopoietic cells slow down retinal degeneration. Because human BM CD34+ hematopoietic cells are not precisely comparable to murine cells, this study examined the effect of intravitreal human BM CD34+ cells on the degenerating retina using a murine model.MethodsC3H/HeJrd1/rd1 mice, immunosuppressed systemically with tacrolimus and rapamycin, were injected intravitreally with PBS (n = 16) or CD34+ cells (n = 16) isolated from human BM using a magnetic cell sorter and labeled with enhanced green fluorescent protein (EGFP). After 1 and 4 weeks, the injected eyes were imaged with scanning laser ophthalmoscopy (SLO)/optical coherence tomography (OCT) and tested with electroretinography (ERG). Eyes were harvested after euthanasia for immunohistochemical and microarray analysis of the retina.ResultsIn vivo SLO fundus imaging visualized EGFP-labeled cells within the eyes following intravitreal injection. Simultaneous OCT analysis localized the EGFP-labeled cells on the retinal surface resulting in a saw-toothed appearance. Immunohistochemical analysis of the retina identified EGFP-labeled cells on the retinal surface and adjacent to ganglion cells. Electroretinography testing showed a flat signal both at 1 and 4 weeks following injection in all eyes. Microarray analysis of the retina following cell injection showed altered expression of more than 300 mouse genes, predominantly those regulating photoreceptor function and maintenance and apoptosis.ConclusionsIntravitreal human BM CD34+ cells rapidly home to the degenerating retinal surface. Although a functional benefit of this cell therapy was not seen on ERG in this rapidly progressive retinal degeneration model, molecular changes in the retina associated with CD34+ cell therapy suggest potential trophic regenerative effects that warrant further exploration.

We report the case of a 69-year-old patient who underwent vitrectomy for vitreomacular traction (VMT) and developed a postoperative macular hole that was observed 1 week after surgery. The hole did not close by in-office fluid-gas exchange alone, but was achieved after repeat surgery with internal limiting membrane (ILM) peeling. Intraoperative OCT (iOCT) images from the first surgery revealed an occult macular hole that formed after VMT release. We discuss how iOCT findings provide insight into the role of the ILM in macular hole formation and emphasize the importance of carefully inspecting iOCT images in real time to avoid missing small but important findings.

Recent advances have made it possible to image the suprachoroidal space, and the understanding of its clinical applications is currently being greatly expanded. This opinion piece covers the advances in imaging techniques that enable the demonstration of the suprachoroidal space, and its implication in various retinal pathologies. It also reviews its potential uses as a route for drug delivery for the treatment of retinal diseases, and its use in innovative surgical techniques. Current research is leading the way for the suprachoroidal space to be an aspect of retinal disease diagnosis, monitoring, medical treatment, and surgical manipulation.

Purpose. To identify retinal pigment epithelium (RPE)/choroid genes and their relevant expression pathways affected by intravitreal injections of dexamethasone and triamcinolone acetonide in mice at clinically relevant time points for patient care. Methods. Differential gene expression of over 34,000 well-characterized mouse genes in the RPE/choroid of 6-week-old C57BL/6J mice was analyzed after intravitreal steroid injections at 1 week and 1 month postinjection, using Affymetrix Mouse Genome 430 2.0 microarrays. The data were analyzed using GeneSpring GX 12.5 and Ingenuity Pathway Analysis (IPA) microarray analysis software for biologically relevant changes. Results. Both triamcinolone and dexamethasone caused differential activation of genes involved in "Circadian Rhythm Signaling" pathway at both time points tested. Triamcinolone (TAA) uniquely induced significant changes in gene expression in "Calcium Signaling" (1 week) and "Glutamate Receptor Signaling" pathways (1 month). In contrast, dexamethasone (Dex) affected the "GABA Receptor Signaling" (1 week) and "Serotonin Receptor Signaling" (1 month) pathways. Understanding how intraocular steroids affect the gene expression of RPE/choroid is clinically relevant. Conclusions. This in vivo study has elucidated several genes and pathways that are potentially altering the circadian rhythms and several other neurotransmitter pathways in RPE/choroid during intravitreal steroid injections, which likely has consequences in the dysregulation of RPE function and neurodegeneration of the retina.

We report a 57-year-old patient with birdshot chorioretinopathy (BCR) who was treated with bilateral Ozurdex injections. The patient's vitritis resolved, and visual acuity improved following this treatment. This is only the second case report focused on the treatment of BCR with Ozurdex and the first to report its use for treating vitritis. A concise review of the literature on the use of intravitreal steroids for this disease is provided. This case serves to report the clinical usefulness of Ozurdex in treating posterior vitritis associated with BCR even in the absence of macular edema.