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S100B is a glial protein, which belongs to calcium-binding protein family. Alterations of S100B level were noted in various neurodegenerative diseases. In a new glaucoma-like animal model S100B was injected intravitreally, which led to neuronal degeneration in retina and optic nerve. The pathological mechanisms are still unknown. Therefore, S100B protein was intravitreally injected in rats. At days 14 and 21, retina, optic nerve, serum, and aqueous humor were investigated. S100B injection led to an increase of retinal NF-κB at day 14. Furthermore, higher IL-1β levels in retina, serum, and aqueous humor were measured. A co-localization of microglia and IL-1β was noted, which correlated with an increased microglia response in retina and optic nerve at day 14. At the same point in time, more apoptotic RGCs and a decline in RGC numbers were observed. At 21 days, this damage was still present, but no signal pathway activations were detectable anymore. Interestingly, macroglia were not affected at any point in time. We conclude that S100B activated the NF-κB signal pathway, which then regulated IL-1β production and release from microglia. A positive feedback loop of IL-1β likely stimulates microglia in a pro-inflammatory manner. These microglia probably induce apoptotic damage in retina and optic nerve. Meanwhile, the injected S100B protein was naturally degraded, which explains the resting state of the pro-inflammatory signal pathways with constant damage later on. The inhibition of S100B release or microglia response could potentially decrease the damage in degenerative diseases, like glaucoma.

Objective: This study was conducted to evaluate the effects of anti-vascular endothelial growth factor (VEGF) antibody (bevacizumab) on vascular leakage and fibrosis in a monkey choroidal neovascularization (CNV) model. The relationship between fibrotic tissue and subretinal hyper-reflective material (SHRM), in optical coherence tomography (OCT) images, was also investigated., Methods: Experimental CNV was induced in male cynomolgus monkeys by laser photocoagulation. Intravitreal injection of bevacizumab at 0.5 mg/eye/dosing was initiated 2 weeks before or after laser irradiation and thereafter, conducted intermittently at 2- or 3-week intervals. Fluorescein fundus angiography (FA) and OCT imaging were conducted weekly from 2 to 7 weeks after laser irradiation. CNV leakage was evaluated by an established grading method using FA images. To assess the fibrosis and scarring, Masson's trichrome specimens of each CNV lesion were prepared, and morphometric analysis was conducted using an image analysis software., Results: The effects of bevacizumab on vascular leakage were shown using an established evaluation method. Morphometric analysis of Masson's trichrome-stained (MT) specimens revealed that collagen fiber synthesis was suppressed by bevacizumab pre-treatment (-29.2%) or post-treatment (-19.2%). SHRM was detected in OCT images in a monkey CNV model, and a significant correlation between the SHRM area in the OCT images and the collagen fiber area in the MT specimens was noted., Conclusion: In the established cynomolgus monkey CNV model, bevacizumab prevented blood leakage but could not completely suppress fibrosis. SHRM in the OCT images reflected retinal fibrous tissue in a laser-induced CNV monkey model. This model might be useful for elucidating the pathology and development therapy for neovascularization or fibrosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Administering anti-vascular endothelial growth factor (anti-VEGF) by intraocular injection has been shown to have a safe systemic profile. Nevertheless, incidents of acute kidney injury following anti-VEGF injection have been reported. We assessed the long-term effect of multiple intravitreal anti-VEGF injections on measures of renal function in patients with diabetes including rate of change of estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (ACR)., Methods: A retrospective review of patients receiving diabetic macular oedema (DMO) treatment was undertaken. Serum creatinine, ACR, number of intravitreal anti-VEGF injections and clinical characteristics were collected from electronic healthcare records (EHR). A co-efficient of eGFR and ACR change with time was calculated over a mean duration of 2.6 years. Regression modelling was used to assess variation in the number of anti-VEGF injections and change in eGFR and ACR., Results: The EHR of 85 patients with DMO (59% male, 78% type 2 diabetes mellitus [T2DM]) were reviewed. On average, 26.8 intravitreal anti-VEGF injections were given per patient over a mean duration of 31 months. No association between increasing number of anti-VEGF injections and rate of eGFR decline (beta = 0.04, 95% confidence intervals [CI]: - 0.02, 0.09; p = 0.22) or ACR change over time (beta = 0.02, CI: - 0.19, 0.23; p = 0.86) was detected, following adjustment for hypertension, cerebrovascular disease, T2DM, and medications taken., Conclusion: Our data suggests regular long-term intravitreal VEGF inhibition does not significantly alter the rate of change in eGFR and/or ACR with increasing number of treatment injections.

Excitotoxicity is known to modulate the nuclear accumulation, and thus activity state, of histone deacetylases (HDACs) in pyramidal neurons. In the retina, deregulation in activity and expression of different HDACs has been linked to pathological conditions such as retinitis pigmentosa, retinal ischemia, glaucoma, and acute optic nerve injury. Up to now, however, the effects of in vivo excitotoxicity on the different HDACs in retinal ganglion cells (RGCs) have not been thoroughly investigated. Here, we injected adult mice intravitreally with N-methyl-D-aspartate (NMDA) as a mean to trigger excitotoxicity-mediated RGC degeneration and we detected time-dependent loss of RGCs at 1 and 7 days after the insult. Further, we characterized the subcellular localization of HDACs belonging to class I (HDAC1, HDAC3), IIa (HDAC4, HDAC5, HDAC7, HDAC9), IIb (HDAC6, HDAC10), and IV (HDAC11) in RGCs. Our analyses revealed a differential pattern of HDACs nuclear distribution in RGCs following excitotoxicity. After 1 day, HDAC3, HDAC5, HDAC6, HDAC7, and HDAC11 showed altered subcellular localization in RGCs while 7 days after the excitotoxic insult, HDAC4 and HDAC9 were the only HDACs displaying changes in their subcellular distribution. Moreover, we found that in vivo selective inhibition of HDAC1/3 or HDAC4/5 via MS-275 (entinostat) or LMK-235, respectively, could prevent ongoing RGC degeneration. In conclusion, our results point towards a role of HDACs in RGC degeneration and identify HDAC1/3 and HDAC4/5 as potential therapeutic targets to treat degenerative retinal diseases.

Background: Age-related macular degeneration (AMD) is the third largest cause of blindness worldwide, accounting for 8.7% of all cases. A considerable number of preventive or therapeutic interventions have been used for AMD., Objective: This study presents a critical view of the interventions that have been assessed through Cochrane systematic reviews., Design and Setting: Review of systematic reviews, conducted in the Discipline of Evidence-Based Medicine, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP)., Methods: Review of Cochrane systematic reviews about interventions for AMD., Results: The 18 systematic reviews included assessed the effects of surgical techniques, laser/photo/radiotherapy, intravitreal injections, systemic drugs and phytotherapy/vitamins/supplements., Conclusion: The Cochrane systematic reviews found evidence that use of bevacizumab, ranibizumab, pegaptanib, laser photocoagulation, photodynamic therapy and multivitamin compounds may present some benefits for treating AMD. There was insufficient evidence for supporting the use of macular translocation, submacular surgery, steroid implantation, radiotherapy, intravitreal aflibercept, interferon alfa, statins or omega-3 fatty acids for treating AMD; or the use of multivitamin antioxidant vitamins or mineral supplementation for preventing AMD. Future randomized controlled trials are imperative to reduce the uncertainty in several clinical questions regarding AMD.

Conventional needle-based approaches in intravitreal drug delivery carry needle-stick-injury risk and could scare patients (belonephobia). Alternatively, our group has explored the application of an electromagnetic needleless injector in this paper. This work aims to improve intravitreal drug delivery, which in the future could assist physicians with automation and benefit patients by providing a needleless approach. Electromagnetic needleless intravitreal injections lack quantification studies. We investigate the delivery properties of the needleless injector where the characterization can be used to refine the design parameters of the prototype in subsequent iterations. Experiments were performed to characterize the injectant delivered from the electromagnetic needleless injector. Penetration tests were conducted to observe the influences of various injection barriers and tissues. Ultrasonic imaging modality was explored for future applications of the prototype. The dispersion of the injectant was controllable where injection depth and distribution is dependent on the input voltage. The synthetic barriers highlighted significant energy losses for penetration (maximum velocity falls from 4.46 to 1.57 mm/s with a 0.1-mm barrier). The biological barriers were difficult to penetrate with the current prototype. Our results indicate that the current electromagnetic injector offers controllable dispersion (depth and distribution) correlated with input voltages, which should have increased injection power for use with biological tissue. Ultrasonic imaging modality produced velocity profiles comparable to the optical approach which is promising for future in vivo studies. The influences of injection barriers should be further investigated in in vivo experiments with ultrasonic imaging modalities. Graphical abstract .

Posterior eye segment diseases are treated through monthly intravitreal injections, that evoke serious side effects. A promising approach to reduce injection frequency consists in producing biodegradable microspheres (MPs) releasing the protein in the vitreous body for long times. Moreover, a rational design of these MPs requires a discouraged diffusion/sedimentation within the intravitreal space, which are detrimental for the vision and the control over drug release kinetics. In this work, poly(lactic-co-glycolic acid) (PLGA)-based MPs encapsulating bovine serum albumin (BSA) were coated with hyaluronic acid (HA) at two molecular weights and tested for their release, diffusion and degradation features in simulated vitreous body (SVB). Results indicate that HA corona prolongs MP degradation time and BSA release. Furthermore, HA coating increased the affinity between MPs and SVB, thereby repressing device transport compared to control PLGA MPs. Results hold promise for the possible application of HA-decorated MPs for intravitreal injection of protein drugs., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: To determine the characteristics of diabetic macular edema (DME) patients refractory to intravitreal bevacizumab (IVB) treatments and an additional dexamethasone implant., Methods: We classified 119 DME patients according to whether or not they are responsive to 3 consecutive monthly anti-VEGF treatments and/or an additional dexamethasone implant. We compared their concentrations of IL (interleukin)-1β, IL-8, IL-10, IL-17, placental growth factor (PlGF), and vascular endothelial growth factor (VEGF) in the aqueous humor as well as their optical coherence tomography (OCT) findings, and baseline characteristics. We used logistic regression analyses to identify preoperative factors related to refractoriness to treatments., Results: Of 119 treatment-naïve DME patients, 50 (42.02%) patients showed responsiveness [central subfield thickness (CST) < 300μm] after 3 IVBs, and 59 (49.58%) patients showed responsiveness after an additional dexamethasone implant, but 10 (8.40%) patients showed CST 300 ≥ μm even after both treatments. Refractory DME patients showed significantly higher number of hyperreflective foci (HF) in the OCT and higher average level of aqueous IL-1β at baseline (p<0.001 and p = 0.042, respectively). In the logistic regression analysis, higher number of HF in the OCT was associated with the refractoriness to both treatments (odds ratio [OR]: 7.03, p = 0.007)., Conclusions: Higher number of HF in the OCT at the initial visit was associated with poor responses to IVBs and an additional dexamethasone implant., Competing Interests: The authors received financial support from the fund of Aju Pharm from Catholic Medical Center Research Foundation in the program year of 2018. The fund is involved with writing the article and publication charge. We declare that all the authors do not have financial or non financial competing interest that occurred within years and outside of 5 year time frame of conducting the research under consideration, or preparing the article for publication. Additionally, we declare that all the authors do not have competing interest regarding employment, consultancy, patents, products in development, marketed products, etc. Also, this does not alter our adherence to PLOS ONE policies on sharing data and materials.

Considerable research over the last few years has revealed dysregulation of growth factors in various retinal diseases, such as glaucoma, diabetic retinopathy and photoreceptor degenerations. The use of messengerRNA (mRNA) to transiently overexpress a specific factor could compensate for this imbalance. However, a critical challenge of this approach lies in the ability to efficiently deliver mRNA molecules to the retinal target cells. In this study we found that intravitreal (IVT) injection is an attractive approach to deliver mRNA to the retina, providing two critical barriers can be overcome: the vitreous and the inner limiting membrane (ILM). We demonstrated that the vitreous is indeed a major hurdle in the delivery of the cationic mRNA-complexes to retinal cells, both in terms of vitreal mobility and cellular uptake. To improve their intravitreal mobility and avoid unwanted extracellular interactions, we evaluated the use of hyaluronic acid (HA) as an electrostatic coating strategy. This HA-coating provided the complexes with a negative surface charge, markedly enhancing their mobility in the vitreous humor, without reducing their cellular internalization and transfection efficiency. However, although this coating strategy allows the mRNA-complexes to successfully overcome the vitreal barrier, the majority of the particles accumulated at the ILM. This study therefore underscores the crucial barrier function of the ILM toward non-viral retinal gene delivery and the need to smartly design mRNA-carriers able to surmount the vitreous as well as the ILM., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Intravitreal injection is one of the major administration routes for the treatment of posterior ocular diseases. Intravitreal therapeutics usually suffer from unsatisfactory efficacy owing to fast clearance from the vitreous humour and insufficient distribution into the retina. Engineered nanoparticles have been applied for specific tissue targeting over the past decades. In this review, we summarize the most recent research utilizing intravitreal nanoparticles to deliver therapeutics to the retina. Herein, the achievement made in preclinical research and challenges remaining in the field are highlighted. Parameters including size, charge, stability and choice of modified ligand on intraocular distribution and transport are also systematically discussed based on a proposed pharmacokinetic model. We provide insights for rational design principles for intravitreal nanoparticles for targeted retinal delivery., (Copyright © 2019. Published by Elsevier Ltd.)

Purpose: To investigate changes in axial length after intravitreal dexamethasone implantation in patients with macular edema., Methods: We performed a prospective comparative study of 46 patients with unilateral macular edema, due to diabetic retinopathy, retinal vein occlusion, and non-infectious uveitis, who underwent dexamethasone implantation. The fellow eyes of the patients were considered the control group. The central macular thickness was measured by spectral-domain optical coherence tomography, and axial length was measured by IOLMaster 700 optical coherence biometry. We compared axial length and central macular thickness values within the groups., Results: In the study group, the baseline central macular thickness was 460.19 ± 128.64 mm, significantly decreasing to 324.00 ± 79.84 mm after dexamethasone implantation (p=0.000). No significant change in central macular thickness measurements was seen in the control group (p=0.244). In the study group, the baseline axial length was 23.16 ± 0.68 mm, significantly increasing to 23.22 ± 0.65 mm after dexamethasone implantation (p=0.039). However, the control group exhibited no significant change in axial length (p=0.123)., Conclusions: In addition to significantly reducing central macular thickness measurements, intravitreal dexamethasone implantation also significantly changes optical biometry-based axial length measurements.

Currently, the two primary patient-derived xenograft (PDX) models of glioblastoma are established through intracranial or subcutaneous injection. In this study, a novel PDX model of glioblastoma was developed via intravitreal injection to facilitate tumor formation in a brain-mimicking microenvironment with improved visibility and fast development. Glioblastoma cells were prepared from the primary and recurrent tumor tissues of a 39-year-old female patient. To demonstrate the feasibility of intracranial tumor formation, U-87 MG and patient-derived glioblastoma cells were injected into the brain parenchyma of Balb/c nude mice. Unlike the U-87 MG cells, the patient-derived glioblastoma cells failed to form intracranial tumors until 6 weeks after tumor cell injection. In contrast, the patient-derived cells effectively formed intraocular tumors, progressing from plaques at 2 weeks to masses at 4 weeks after intravitreal injection. The in vivo tumors exhibited the same immunopositivity for human mitochondria, GFAP, vimentin, and nestin as the original tumors in the patient. Furthermore, cells isolated from the in vivo tumors also demonstrated morphology similar to that of their parental cells and immunopositivity for the same markers. Overall, a novel PDX model of glioblastoma was established via the intravitreal injection of tumor cells. This model will be an essential tool to investigate and develop novel therapeutic alternatives for the treatment of glioblastoma.

The present review focuses on recent clinical trials that analyze the efficacy of intravitreal therapeutic agents for the treatment of dry age-related macular degeneration (AMD), such as neuroprotective drugs, and complement inhibitors, also called immunomodulatory or anti-inflammatory agents. A systematic literature search was performed to identify randomized controlled trials published prior to January 2019. Patients affected by dry AMD treated with intravitreal therapeutic agents were included. Changes in the correct visual acuity and reduction in geographic atrophy progression were evaluated. Several new drugs have shown promising results, including those targeting the complement cascade and neuroprotective agents. The potential action of the two groups of drugs is to block complement cascade upregulation of immunomodulating agents, and to prevent the degeneration and apoptosis of ganglion cells for the neuroprotectors, respectively. Our analysis indicates that finding treatments for dry AMD will require continued collaboration among researchers to identify additional molecular targets and to fully interrogate the utility of pluripotent stem cells for personalized therapy.

Aims: To analyze contrast sensitivity of intravitreal bevacizumab injections with optimizing glycemic control versus optimizing glycemic control (in combination with sham injections) in eyes with Diabetic Macular Edema (DME)., Design: Prospective, interventional, masked, randomized controlled trial., Methods: Forty-one eyes of 34 patients with type 2 diabetes mellitus and DME with glycated hemoglobin (HbA1c) < 11% received either intravitreal bevacizumab injection (Group 1) or sham injection (Group 2) at 0 and 6 weeks along with optimizing glycemic control. Mean change in best-corrected visual acuity (BCVA), contrast sensitivity (CS), optical coherence tomography (OCT)-measured by central macular thickness (CMT) were compared and correlated at baseline, 2, 6 and 12 weeks., Results: The study showed a mean CS improved in group 1 from 1.14 ± 0.36 logCS to 1.32 ± 0.24 logCS and also in group 2 from 1.11 ± 0.29 logCS to 1.18 ± 0.29 logCS at 12 weeks (P = 0.12). CS and CMT promptly decreased in group 1 compared to group 2 at 2 weeks (ΔCS = 0.15 ± 0.25 vs. 0.03 ± 0.15 logCS; P = 0.04; ΔCMT = 116 ± 115 vs. 17 ± 71 μm; P = 0.01). There was a mean reduction of approximately 0.5% in HbA1c levels in both groups at 12 weeks (P = 0.002)., Conclusion: The use of bevacizumab in combination with optimizing glycemic control results in earlier improvement of contrast sensitivity in type 2 diabetes patients with DME. However, the optimizing glycemic control itself has shown also to be effective at 12 weeks. ClinicalTrials.gov Identifier: NCT02308644., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The intravitreal route faces many challenges in rapidly and effectively reaching posterior eye pathology, with administered therapeutics experiencing non-specific distribution around and premature clearance from ocular tissues. Nanobubbles and ultrasound may improve outcomes of intravitreally administered drugs by influencing the directionality of drug-containing particle migration. In this study, we assessed the impact of trans-scleral or corneal ultrasound application on the distribution of intravitreally-injected nanobubbles. Rhodamine-tagged gas entrapped nanobubble formulations were prepared and injected into ex vivo bovine and porcine eyes and subjected to ultrasound (1 MHz, 0-2.5 W/cm 2 , 50-100% duty, 60 s). Bovine eyes were partially dissected to visualize the vitreous humor and particle migration was evaluated via optical fluorescence spectroscopy. Directional migration in porcine eyes was evaluated using a snap freezing protocol complemented by quantification of regional fluorescence. The impact on nanobubble migration following pars-plana injection and sequential ultrasound cycle application from scleral or corneal-surface positions was also assessed. Administration of ultrasound significantly enhanced the directional migration of nanobubbles in both ex vivo models, with multiple corneal ultrasound cycles promoting greater migration of dye-filled nanobubbles to posterior regions of the vitreous. Moreover, particles moved in a directional manner away from the ultrasound wave source demonstrating an ability to effectively control the rate and path of nanobubble migration. These findings establish an encouraging new and safe modality enabling rapid distribution of intravitreally-injected therapeutics where expeditious therapeutic intervention is warranted., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This retrospective study was to compare the efficacy of intravitreal injection of ranibizumab and aflibercept for patients with pachychoroid neovasculopathy. 54 eyes were initially treated with 3 monthly loading injections of ranibizumab or aflibercept. Treatment switching from ranibizumab to aflibercept, and aflibercept to photodynamic therapy was done at 3 months in case of incomplete fluid absorption. At 3 months, the rate of complete fluid absorption was significantly higher in the aflibercept-treated group than in the ranibizumab-treated group (82.6% vs 51.6%, p = 0.018). The mean reduction of subfoveal choroidal thickness was significantly greater in the aflibercept group than in the ranibizumab group (-35 µm vs -9 µm, p = 0.013). There was no significant difference between the two groups in terms of visual improvement or decrease in central macular thickness. Complete fluid absorption was achieved after switching from ranibizumab to aflibercept in 13 of 15 eyes (86.7%). Adjunctive photodynamic therapy was required in 6 eyes. In conclusion, treatment mainly with anti-vascular endothelial growth factor effectively improved visual acuity within 12 months (from 20/56 to 20/44 at 3 months and to 20/36 at 12 months). Aflibercept was superior to ranibizumab in achieving dry macula and reducing choroidal thickness at 3 months.

This study aimed to investigate whether the transplantation of genetically engineered bone marrow-derived mesenchymal stromal cells (MSCs) to overexpress brain-derived neurotrophic factor (BDNF) could rescue the chronic degenerative process of slow retinal degeneration in the rd6 (retinal degeneration 6) mouse model and sought to identify the potential underlying mechanisms. Rd6 mice were subjected to the intravitreal injection of lentivirally modified MSC-BDNF or unmodified MSC or saline. In vivo morphology, electrophysiological retinal function (ERG), and the expression of apoptosis-related genes, as well as BDNF and its receptor (TrkB), were assessed in retinas collected at 28 days and three months after transplantation. We observed that cells survived for at least three months after transplantation. MSC-BDNF preferentially integrated into the outer retinal layers and considerably rescued damaged retinal cells, as evaluated by ERG and immunofluorescence staining. Additionally, compared with controls, the therapy with MSC-BDNF was associated with the induction of molecular changes related to anti-apoptotic signaling. In conclusion, BDNF overexpression observed in retinas after MSC-BDNF treatment could enhance the neuroprotective properties of transplanted autologous MSCs alone in the chronically degenerated retina. This research provides evidence for the long-term efficacy of genetically-modified MSC and may represent a strategy for treating various forms of degenerative retinopathies in the future.

Background and Objectives: Ozurdex intravitreal injection is performed via a patented injection device. However, there is a common misconception among ophthalmologists regarding the relation between the speed of applicator button depression and the speed of pellet injection., Patients and Methods: Six dexamethasone intravitreal implants were injected into a calibrated ex vivo water bath. Three of the pellets were injected via rapid compression, whereas the other three implants were injected using a 3-second compression technique. The procedures were recorded using high-speed photography followed by calculation of pellet velocity and impact force., Results: The mean impact velocity and force of the pellet insertion is significantly higher in the fast injection group compared to the slow injection group., Conclusions: By depressing the Ozurdex implant injector during a 3-second time interval, the impact force of the implant pellet is reduced by about 95%. This new technique will theoretically reduce the risk of retinal injury and vitreous hemorrhage from Ozurdex injections. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e23-e25.]., (© 2019 Krambeer, Wannamaker, Tie, et al.)

The effect of triamcinolone acetonide (TA) on the peripheral retinochoroidal thickness was determined after pars plana vitrectomy (PPV) with scatter photocoagulation in eyes with proliferative diabetic retinopathy. The peripheral retinochoroidal thickness was measured at 5 mm from the limbus in the four quadrants using anterior segment optical coherence tomography before, and 3 days, and 1 and 2 weeks after the surgery. The total peripheral thickness was significantly thicker than the baseline thickness after PPV alone (P < 0.001; 18 eyes), PPV combined with intravitreal TA injection (IVTA; P = 0.011; 19 eyes), and PPV combined with sub-tenon TA injection (STTA; P = 0001; 23 eyes). The total peripheral thickness in the PPV group at 3 days after surgery was significantly thicker than that of the PPV + IVTA (P = 0.015) and of the PPV + STTA groups (P = 0.016). Multiple linear regression analyses showed that the injection of TA by the two routes and the number of photocoagulation burns were significantly correlated with the total peripheral thicknesses at 3 days after the surgery. The results indicate that the PPV with large number of intraoperative scatter photocoagulation burns caused an increase in the total peripheral thickness and an administration of either IVTA and STTA can reduced the degree of thickening.

Objective: This study aimed to examine whether DC101 (anti-VEGFR2 antibody)- modified micelles have applications as novel drug delivery devices, which allow small molecule antiangiogenic agents to deliver to angiogenic sites on a murine laser-induced choroidal neovascularization (CNV) model., Materials and Methods: CNV was induced by photocoagulation on the unilateral eye of each mouse under anesthesia. Immediately after laser coagulation, E7974-loaded DC101-modified micelles and motesanib-loaded DC101-modified micelles were intravitreally administrated. Two weeks after photocoagulation, CNV was visualized using fluorescein-conjugated dextran (MW=2,000 kDa), and the CNV area was measured in retinal pigment epithelium (RPE)-choroidal flat mounts., Results: Intravitreal administration of both DC101-modified micelles loaded with E7974 at 2 µM and motesanib at 2 µM significantly reduced CNV area in the murine laser-induced CNV model at a clearly lower concentration than the effective dose of each agent., Conclusion: These results suggest that DC101-modified micelle might be effective drug carrier system for treating CNV and other ocular angiogenic diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: To compare effects of 5% topical povidone iodine with prophylactic topical azithromycin and moxifloxacin on bacterial flora in patients undergoing intravitreal injection., Methods: A total of 132 patients were randomly assigned to receive treatment with azithromycin or moxifloxacin, or no treatment (control group). In total, 528 specimens were obtained at the time of admission, 4 days before intravitreal injection, 4 days after intravitreal injection, and 8 days after intravitreal injection. Samples were immediately sent to the microbiology laboratory for incubation., Results: The microorganism observed most frequently was coagulasenegative Staphylococcus (23.8%). When the results of samples obtained on Day 4 before injection were assessed, growth of coagulase-negative Staphylococcus was significantly lower in the moxifloxacin group, compared with controls (p=0.049). Acinetobacter baumannii continued to grow after administration of azithromycin (p=0.033). When the results of four days after intravitreal injection were evaluated, growth of coagulase-ne gative Staphylococcus was higher in controls, compared with patients who received azithromycin or moxifloxacin (p=0.004). Eradication rate was significantly higher in the moxifloxacin group than in the control group (p=0.001). Samples obtained on Day 8 after intravitreal injection showed similar levels of bacterial growth in all groups (p=0.217)., Conclusion: Moxifloxacin was more effective than 5% povidone iodine in controlling the growth of conjunctival bacterial flora. Use of moxifloxacin in combination with 5% povidone iodine resulted in a synergistic effect.

Objective: N-methyl-D-aspartate (NMDA) excitotoxicity has been proposed to mediate apoptosis of retinal ganglion cells (RGCs) in glaucoma. Taurine (TAU) has been shown to have neuroprotective properties, thus we examined anti-apoptotic effect of TAU against retinal damage after NMDA exposure., Methodology: Sprague-Dawley rats were divided into 5 groups of 33 each. Group 1 was administered intravitreally with PBS and group 2 was similarly injected with NMDA (160 nmol). Groups 3, 4 and 5 were injected with TAU (320 nmol) 24 hours before (pre-treatment), in combination (co-treatment) and 24 hours after (post-treatment) NMDA exposure respectively. Seven days after injection, rats were sacrificed; eyes were enucleated, fixed and processed for morphometric analysis, TUNEL and caspase-3 staining. Optic nerve morphology assessment was done using toluidine blue staining. The estimation of BDNF, pro/anti-apoptotic factors (Bax/Bcl-2) and caspase-3 activity in retina was done using ELISA technique., Results: Severe degenerative changes were observed in retinae after intravitreal NMDA exposure. The retinal morphology in the TAU pre-treated group appeared more similar to the control retinae and demonstrated a higher number of nuclei than the NMDA group both per 100 μm length (by 1.5-fold, p < 0.001) and per 100 μm 2 area (by 1.41-fold, p < 0.05) of the GCL. After NMDA exposure, visible axonal swelling was observed in optic nerve sections. In comparison with the changes observed in the NMDA treated group, the TAU treated group showed fewer prominent changes; axonal swelling was less frequent and less marked. Additionally, no marked glial cell changes were observed in the TAU-pretreated group. All TAU treated groups, particularly the pre-treated group, showed a significant decrease in the NMDA-induced optic nerve damage, with a 50% reduction (p < 0.001) in the mean grading compared to NMDA group. For the same, there was 25% decrease in co- and post-treatment groups, as compared with the NMDA group. Pre-treatment with TAU abolished apoptotic response to NMDA as indicated by decrease in the number of TUNEL- and caspase-3-positive cells. TAU pre-treatment also increased the Bcl-2 level (by 2.80-fold, p < 0.001) and decreased the level of Bax (by 34%, p < 0.01), and activity of caspase-3 (by 36%, p < 0.001) compared to NMDA group., In Conclusion: our study revealed that pre-treatment with TAU prevents NMDA-induced retinal cell apoptosis more effectively than co- and post-treatment with TAU., (Copyright © 2018 Elsevier B.V. All rights reserved.)

BACKGROUND The aim of this study was to compare the alterations in intraocular pressure (IOP) values during the early postoperative period after intravitreal ranibizumab, aflibercept, or dexamethasone implant injections. MATERIAL AND METHODS In this retrospective study, a total of 188 patients were grouped into 3 groups: the ranibizumab group, the aflibercept group, and the dexamethasone group. Ocular axial length (AXL) and anterior chamber depth (ACD) were measured in the pre-injection period. IOP was measured just before the injection at 1 minute,10 minutes, 1 hour, 1 day, and 1 month after injection. RESULTS There was a transient peak in the ranibizumab group and the aflibercept group at 1 minute that started to decrease at 10 minutes and IOP values returned to preoperative values at approximately 1 hour. Similar alterations were also determined for the dexamethasone group with a lesser increase noted. In the correlation analysis, only alterations in IOP levels at 1 minute were negatively correlated with preoperative AXL values. There was not any correlation between preoperative AXL or ACD values and IOP alterations at any other time points. CONCLUSIONS There was a sudden, transient increase in IOP values after intravitreal ranibizumab or aflibercept injections; which return to normal values in a short time without requirement of any medical treatments. This transient peak was determined to be negatively correlated with the preoperative AXL.

Purpose: To evaluate the efficacy of dexamethasone intravitreal implants (DEX implant) in patients with treatment-resistant macular edema (ME) owing to branch and central retinal vein occlusion (BRVO/CRVO), and the influence of prior vitrectomy on this treatment. Methods: Multicenter retrospective chart review was performed on 40 CRVO and 32 BRVO eyes with persistent ME despite intravitreal anti-vascular endothelial growth factor agents and/or intravitreal triamcinolone, and/or laser therapy. Each patient received ≥1 dexamethasone 700 μg implant between March 2011 and December 2015. Thirteen patients underwent prior vitrectomy. Data were collected on best-corrected visual acuity (BCVA), central macular thickness (CMT), time to relapse, and adverse events. Results: At the end of follow-up, BRVO eyes had a lesser CMT reduction from baseline compared to CRVO eyes (-122.50 ± 152.47 μm and -202.26 ± 194.09 μm, respectively). Neither BRVO nor CRVO eyes had a sustained BCVA benefit ( P  = 0.7041 and P  = 0.7027, respectively). Vitrectomized and nonvitrectomized eyes overall had a sustained significant CMT reduction throughout the study with -192.46 ± 172.62 μm and -164.02 ± 180.36 μm, respectively, at final follow-up. Similar time to relapse of 24.4 ± 6.5 and 23.3 ± 13.5 weeks, respectively, was observed. By the end of follow-up, BCVA had only improved in vitrectomized eyes. However, multivariable regression analyses showed no significant association between vitrectomy status and CMT or BCVA change after the first and last injection. Cataract formation and ocular hypertension occurred in 25% and 17%, respectively. Conclusions: Multiple DEX implant are effective in reducing CMT in patients resistant to previous treatments and appear to be similarly effective in vitrectomized and nonvitrectomized eyes.

Purpose: To evaluate safety and efficacy of the vascular endothelial growth factor binding protein abicipar pegol (abicipar) versus ranibizumab for neovascular age-related macular degeneration. Methods: Phase 2, multicenter, randomized, double-masked comparison (REACH study, stage 3). Patients ( n  = 64) received intravitreal injections of abicipar 1 mg or 2 mg at baseline, week 4, and week 8 (3 injections) or ranibizumab 0.5 mg at baseline and monthly (5 injections). Results: In the abicipar 1 mg ( n  = 25), abicipar 2 mg ( n  = 23), and ranibizumab ( n  = 16) arms, respectively, least-squares mean best-corrected visual acuity (BCVA) change from baseline was +6.2, +8.3, and +5.6 letters at week 16 (primary endpoint) and +8.2, +10.0, and +5.3 letters at week 20. Least-squares mean central retinal thickness (CRT) reduction from baseline was 134, 113, and 131 μm at week 16 and 116, 103, and 138 μm at week 20. Intraocular inflammation adverse events (AEs), reported in 5/48 (10.4%) abicipar-treated patients, resolved without sustained vision loss or other sequelae. Conclusions: Abicipar demonstrated durability of effect: BCVA and CRT improvements were similar between abicipar and ranibizumab at weeks 16 and 20 (8 and 12 weeks after the last abicipar injection and 4 weeks after the last ranibizumab injection). No serious AEs were reported.

Background: To evaluate the possible effects of multiple intravitreal anti-vascular endothelial growth factor (VEGF) injections on intraocular pressure (IOP)., Methods: This study included 50 eyes of 50 patients who underwent multiple (≥ 10 injections) intravitreal anti-VEGF injections in one eye with age-related macular degeneration, diabetic macular edema or retinal vein occlusion. IOP was recorded after every injection on the first postoperative day. IOP > 21 mmHg was regarded as abnormal. For statistical analysis, the IOP was correlated with the number of injections., Results: A total of 669 IOP-measurements (mean 13.4 treatment/eye) were analyzed. No IOP-elevation was recorded in 43 eyes (86%). Transient elevated IOP > 21 mmHg was measured after 19 intravitreal injections (2.8%, one patients with 8 IOP elevations). In general, there was no increasing risk of IOP elevation with time, no case of sustained IOP elevation and no additional long term glaucoma treatment necessary. Eyes with pre-existing glaucoma were significantly more affected from transient IOP-elevation than non-glaucoma eyes (5.5 vs. 2.2%)., Conclusions: Multiple anti-VEGF injections are not associated with an increased risk of sustained IOP-elevation. On the other hand, individual risk factors exist and predispose to IOP-elevation (e.g., pre-existing glaucoma)., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Stuttgart · New York.)

Fungal endophthalmitis remains a significant cause of vision impairment and blindness. Moreover, the prognosis is poor, in part due to delay in diagnosis and to limited availability of effective antifungal agents with good ocular penetration. Thus, it is imperative to evaluate the therapeutic efficacy in fungal endophthalmitis of newer antifungal agents. In this study, we assessed the efficacy of isavuconazole in treating Aspergillus fumigatus endophthalmitis in an exogenous mouse model of the disease. Briefly, endophthalmitis was induced by intravitreal (IVT) injection of A. fumigatus spores into immunocompetent C57BL/6 (B6) mouse eyes. Mice were randomized into five groups that received isavuconazole via (i) oral gavage, (ii) IVT injections, (iii) intravenous injection, (iv) IVT injection followed by oral gavage, and (v) IVT injection followed by intravenous injection. Our data showed that isavuconazole treatment via all routes reduced fungal burden in A. fumigatus -infected eyes. This coincided with the preservation of retinal structural integrity (histology analysis) and retinal function (electroretinography [ERG] analysis), resulting in significantly improved disease outcome. Furthermore, isavuconazole treatment reduced the levels of inflammatory cytokines (tumor necrosis factor α [TNF-α], interleukin 1β [IL-1β], and IL-6) and cellular infiltration in the eyes. Notably, oral administration of isavuconazole was as effective in ameliorating endophthalmitis as intravitreal injection of the drug. Collectively, our study demonstrates that isavuconazole is effective in treating A. fumigatus endophthalmitis in mice, indicating its potential use in human ocular infections., (Copyright © 2018 American Society for Microbiology.)

BACKGROUND This article discusses the effectiveness of phacoemulsification cataract surgery with intraocular lens implantation in patients with wet age-related macular degeneration in the inactive phase of the disease. MATERIAL AND METHODS Forty-nine patients (50 eyes) aged 78.94±5.54 years, previously treated with intravitreal injections of anti-vascular endothelial growth factor agents, were qualified for a prospective, randomized 12-month study. The participants were divided into 2 groups. Group I consisted of 25 patients (25 eyes) who were subjected to phacoemulsification cataract surgery. Group II consisted of 24 patients (25 eyes) who were not subjected to phacoemulsification cataract surgery despite having a lens opacity of grade II or higher according to the Lens Opacities Classification System. RESULTS After 12 months of follow-up, patients in group I gained on average 8.04 letters (p<0.001). Furthermore, 20% of the eyes had a significant improvement in best corrected visual acuity of ≥15 Early Treatment of Diabetic Retinopathy Study Chart letters. Patients in group II lost on average 1.96 letters (p>0.05). No significant differences between central retinal thickness values in either group (p>0.05) were noted. The mean number of intravitreal injections of anti-vascular endothelial growth factor agents during the study was 2.64±1.98 in group I and 2.92±2.40 in group II (p>0.05). CONCLUSIONS Phacoemulsification performed in eyes with wet age-related macular degeneration during the inactive phase of the disease significantly improves visual acuity. In addition, it does not significantly influence the frequency of intravitreal injections of anti-vascular endothelial growth factor agents or disease activity.

Background/aims: To describe an alternative technique for avoiding contact with the lids and lashes, without the use of a lid speculum, during intravitreal anti-vascular endothelial growth factor injections., Methods: Retrospective case series of all patients undergoing intravitreal injections of bevacizumab and ranibizumab, with the lid splinting retraction technique from January 2010 to December 2015. Injections performed by six vitreoretinal specialists were included. The key preinjection ocular surface preparation includes topical anaesthetic, 5% povidone-iodine and a subconjunctival injection of 2% lidocaine with epinephrine. A second instillation of 5% povidone-iodine is given and the intravitreal injection is then performed. No lid speculum is used. A search of the electronic medical records identified patients diagnosed with postinjection endophthalmitis and charts were reviewed to ensure inclusion criteria were met. The main outcome measure was incidence of postinjection endophthalmitis., Results: A total of 78 009 consecutive intravitreal injections were performed, of which 22 207 were bevacizumab and 55 802 were ranibizumab. In this cohort of patients (n=6320), 12 cases of endophthalmitis developed, corresponding to a rate of 0.015%., Conclusions: The technique of eyelid retraction for intravitreal injection has a low rate of endophthalmitis, similar to the reported rates using a metal lid speculum. This is beneficial for both the physician and the patient as it minimises patient discomfort as well as the duration of the procedure. To our knowledge, this is one of the largest studies performed to date evaluating intravitreal injection-related endophthalmitis., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The goal of this report is to provide a review on different strategies for the use of pro re nata (PRN) and treat and extend (T&E) regimens with intravitreal anti-VEGF agents (bevacizumab, ranibizumab or aflibercept) in patients with retinal diseases such as neovascular AMD, diabetic macular oedema and macular oedema due to retinal vein occlusion. The main focus is to present the effectiveness and visual outcomes of both PRN and T&E regimens in the main pivotal trials and studies based on currently available evidence. We also discuss the advantages and disadvantages of both regimens, as well as monitoring and treatment of the disease, including treatment intervals and injection frequency. Currently there is increasing interest in establishing a regimen which offers the best visual outcome with lower injection frequency, and with reduced treatment burden by individualising treatment intervals and minimising the number of clinic visits and costs. Studies have shown that the PRN regimens in a clinical setting are insufficient in assuring the best visual outcome. The PRN regime requires frequent clinic visits to monitor disease status and intravitreal treatment if needed in a reactive approach. Individualised T&E regimens can improve visual outcome and require fewer injections than those administered in a monthly regimen and fewer monitoring visits than those in a PRN regimen., Competing Interests: Nein., (Georg Thieme Verlag KG Stuttgart · New York.)

Aim: We aimed to investigate the effectivity of the 0.0625 mg dose of bevacizumab in patients with retinopathy of prematurity (ROP) and compare the results with 0.625 mg dose of intravitreal bevacizumab (IVB) injection., Methods: The medical records of the patients with type 1 ROP who received IVB monotherapy were retrospectively reviewed. Demographic and clinical characteristics of the patients were recorded. The patients were classified into two groups with respect to received dose of bevacizumab as follows: group F (n = 46) (full dose of bevacizumab-0.625 mg/0.025 ml) and group L (n = 45) (low dose (one tenth) of bevacizumab-0.0625 mg/0.025 ml)., Results: Both treatment dose regimens have similar outcomes. Moreover, the mean retinal vascularization time seemed to be significantly higher in group F compared to group L, 168 ± 65 and 97 ± 29 days, respectively (p < 0.001). Disappearance of plus sign is observed earlier in group F (2.45 ± 1.7 vs 3.66 ± 2.46 days, respectively, p = 0.03)., Conclusions: The low dose (0.0625 mg) of IVB treatment was effective as full (0.625 mg) dose in ROP treatment. Moreover, our results showed that low-dose treatment might provide faster retinal vascularization than the regular used dose. On the other hand, disappearance of the plus sign takes longer time in patients treated with low dose compared to eyes treated with full dose of IVB that should be taken into account.

Background: Recent years have seen major changes in the diagnosis and treatment of solid intraocular tumors, mainly owing to an improved molecular biological understanding of their pathogenesis, new therapeutic approaches for the local treatment of tumors in children, and long-term follow-up observations in clinical trials., Methods: This review is based on pertinent publications retrieved by a selective search in PubMed., Results: Retinoblastoma is the most common type of primary intraocular tumor, with approximately 8000 new cases per year around the world, while malignant melanoma of the uvea is the most common primary intraocular tumor in adults, with approximately 7000 new cases per year around the world. Intraocular metastases of malignant tumors are ten times more common, in terms of incidence, than primary intraocular tumors and are therefore the most common intraocular tumors overall. Improved methods of intraocular biopsy, diagnostic imaging, and molecular genetic investigation have led to steady improvement in clinical and predictive diagnostic assessment. In the treatment of retinoblastoma, local techniques including brachytherapy and intra-arterial and intravitreal chemotherapy play a prominent role. Prognostic molecular-genetic testing now enables the highly selective identification of uveal melanomas that have a high potential to metastasize. Cutaneous and uveal melanomas differ both in their clinical behavior and in their basic biological features; to date, effective systemic treatment has been established for melanoma of the skin, but not for metastatic melanoma of the uvea. Intraocular metastases are common and often the initial manifestation of an extraocular tumor, particularly lung cancer., Conclusion: Modern diagnostic and therapeutic concepts for intraocular tumors can only be implemented through the close interdisciplinary collaboration of ophthal - mologists, oncologists, radiologists, radiotherapists, pathologists, and human geneticists.

Blinding retinal diseases become more epidemic as the population ages. These diseases, such as diabetic retinopathy and macular edema, are of chronic nature and require protracted drug presence at the disease site. A sustained intravitreal porous silicon delivery system with dexamethasone (pSiO 2 -COO-DEX) was evaluated in a new rabbit model of proliferative vitreoretinopathy (PVR) in a real treatment design. In contrast to the pretreatment design model, pSiO 2 -COO-DEX was intravitreally injected into the eyes with active inflammation. Subretinal injection of vascular endothelial growth factor (VEGF) and Matrigel induced a late-onset vitreoretinal inflammation that gradually developed into PVR. This method mimics the human disease better than PVR induced by either intravitreal cell injection or trauma. The pSiO 2 -COO-DEX intervened eyes had minimal PVR, while balanced saline solution or free dexamethasone intervened eyes had significantly more PVR formation. In addition, adding VEGF to the Matrigel for subretinal injection induced greater inflammation and retinal neovascularization in comparison to only Matrigel injected under the medullary ray. Clinical and pathological examinations, including fundus fluorescein angiography and optical coherence tomography, confirmed these changes. In the current study, neither subretinal injection of Matrigel or subretinal injection of VEGF and Matrigel induced choroidal neovascularization. However, the current PVR model demonstrates a chronic course with moderate severity, which may be useful for drug screening studies.

This study was aimed at investigating the role of IVI angle on the induced stresses and deformations among the components of the eye. Thereafter, the most optimal angle of IVI to minimize the complications of post IVI at the injection site on a basis of the computed stresses via a Fluid-Structure Interaction (FSI) computational model was proposed. IntraVitreal Injection (IVI) is broadly employed as a principal treatment of vascular vitro-retinal diseases. So far, there have been reports regarding the complications of post IVI and determine them as severe uveitis, tractional retinal detachment, IntraOcular Pressure (IOP) elevation as well as ocular haemorrhage. However, there is a lack of knowledge on how to reduce the subsequent ocular tissue damage and patient symptoms in the injection site. Seven different IVI angles were simulated, including 0∘, 15∘, 30∘, 45∘, 60∘, 75∘, and 90∘, through the Finite Element (FE) code; and the term, 'post IVI complication' or 'injury', in the results was interpreted as the level of maximal principal stress in the eye components. The results revealed the lowest amount of stresses at the angle of 45∘ in respect to the horizontal line (acute to the surface of the sclera) for the lens, iris, vitreous body, aqueous body, ciliary body, sclera, retina, and choroid. The cornea illustrated the same amount of stress at the angles of 45∘, 60∘, 75∘, and 90∘ with the highest one at the IVI angle of 30∘. The lowest and the highest stresses among the eye components regardless of IVI angle were observed in the choroid and retina/sclera, respectively, which imply the importance of the IVI angle on the stresses of these eye components. The findings of the contemporary research revealed that the IVI angle of 45∘ would trigger less post IVI complications and, as a result, a more effective surgery outcome compared to the other angles, i.e., 0∘, 15∘, 30∘, 60∘, 75∘, and 90∘.

Gene therapy in ophthalmology has developed rapidly, and there has been a breakthrough in the treatment of Leber's hereditary optic neuropathy. After receiving an intravitreal injection of rAAV2-ND4, patients followed up over a certain time period showed a definite increase in visual acuity. Visual acuity testing is critical for assessing the efficacy of rAAV2-ND4 intravitreal injection.

The burden of intravitreal injections has increased tremendously over the past few years. Since traditionally the operation theatre setup is currently used for this procedure, it is increasingly becoming difficult to manage such a patient load in the theatres. To overcome this challenge, office-based setup for intravitreal injection was started. This study was planned to determine the incidence of endophthalmitis after office-based intravitreal bevacizumab injection and to compare it with previously reported incidence of endophthalmitis after operation theatre-based intravitreal injections. The study was conducted at Al-Ehsan Eye Hospital, Lahore, Pakistan, from July 2015 to June 2016, and comprised patients who received intravitreal injections of bevacizumab (Avastin) for different ocular indications. A total of 1,047 intravitreal injections were given in an office-based set-up. Of them, 2(0.19%) cases of clinically suspected endophthalmitis were identified. Office-based set-up for intravitreal bevacizumab injection was found to have comparable safety profile with traditional operation theatre-based set-up.

Background: Retinal angiomatous proliferations (RAP) are a subgroup of exsudative or "wet" age-related macular degeneration (wAMD) with devastating reduction of visual acuity in later stages. Intravitreal ranibizumab provides good therapy, but is considered to be less effective than in other choroidal neovascularizations (CNV)., Objective: We investigated the efficacy of ranibizumab in late-stage III RAP with retinochoroidal anastomosis compared to the outcome of other CNV lesions., Materials and Methods: The data of all patients with wAMD treated with ranibizumab were retrospectively analyzed. Patients were divided into groups depending on the lesion type into RAP (identified and selected clinically, proven by fluorescein angiography) and CNV lesions (identified by fluorescein angiography only) named occult, minimally and predominantly classic groups. The best-corrected visual acuity (BCVA) was obtained before (at the timepoint "diagnosis"), during (1st, 2nd, and 3rd injection), and after upload ("1st control")., Results: Before first injection, visual acuity decreased in all groups (0.73 to 0.78 logMAR for all CNV, 0.95 to 1.02 logMAR for RAP). During upload there was no further decline in visual acuity but no improvement as well up to the 1st control visit in the RAP group (1.02 to 1.03 logMAR), but a statistically significant increase in all other groups (0.78 to 0.67 logMAR)., Conclusion: Treatment of late-stage III RAP with ranibizumab is effective. Stabiliziation of visual acuity can be achieved, but-in contrast to other forms of CNV lesions-no further improvement. Therefore, patients with this special form need to be identified and treated as early as possible.

Background: Drug ocular toxicity is a field that requires attention. Clindamycin has been injected intravitreally to treat ocular toxoplasmosis, the most common cause of eye posterior segment infection worldwide. However, little is known about the toxicity of clindamycin to ocular tissues. We have previously showed non intraocular toxicity in rabbit eyes of poly(lactic-co-glycolic acid) (PLGA) implants containing clindamycin hydrochloride (CLH) using only clinical macroscotopic observation. In this study, we investigated the in vivo biocompatibility of CLH-PLGA implants at microscotopic, cellular and molecular levels., Methods: Morphology of ARPE-19 and MIO-M1 human retinal cell lines was examined after 72 h exposure to CLH-PLGA implant. Drug delivery system was also implanted in the vitreous of rat eyes, retinal morphology was evaluated in vivo and ex vivo. Morphology of photoreceptors and inflammation was assessed using immunofluorescence and real-time PCR., Results: After 72 h incubation with CLH-PLGA implant, ARPE-19 and MIO-M1 cells preserved the actin filament network and cell morphology. Rat retinas displayed normal lamination structure at 30 days after CLH-PLGA implantation. There was no apoptotic cell and no loss in neuron cells. Cones and rods maintained their normal structure. Microglia/macrophages remained inactive. CLH-PLGA implantation did not induce gene expression of cytokines (IL-1β, TNF-α, IL-6), VEGF, and iNOS at day 30., Conclusion: These results demonstrated the safety of the implant and highlight this device as a therapeutic alternative for the treatment of ocular toxoplasmosis.

Purpose: To study the suitability of injectable microspheres based on poly(ester amide) (PEA) or poly lactic-co-glycolic acid (PLGA) as potential vehicles for intravitreal drug delivery in rat eyes. Dexamethasone-loaded PEA microspheres (PEA + DEX) were also evaluated., Methods: Forty male Sprague Dawley rats were divided into four groups that received different intravitreally injected microspheres: PEA group (n = 12); PLGA group (n = 12); PEA + DEX group (n = 8); and control group (no injection, n = 8). Electroretinography (ERG), fundus autofluorescence (FAF), and spectral domain optical coherence tomography (sdOCT) were performed at baseline, weeks 1 and 2, and months 1, 2, and 3 after intravitreal injection. Eyes were histologically examined using light microscopy and transmission electron microscopy at the end of the in vivo study., Results: There were no statistically significant changes in ERG among the groups. Abnormal FAF pattern and abnormal deposits in OCT were observed after injection but almost completely disappeared between week 2 and month 3 in all injected groups. GFAP staining showed that Müller glia cell activation was most pronounced in PLGA-injected eyes. Increased cell death was not observed by TUNEL staining at month 1. In electron microscopy at month 3, the remnants of microparticles were found in the retinal cells of all injected groups, and loss of plasma membrane was seen in the PLGA group., Conclusions: Although morphological changes such as mild glial activation and material remnants were observed histologically 1 month and 3 months after injection in all injected groups, minor cell damage was noted only in the PLGA group at 3 months after injection. No evidence of functional abnormality relative to untreated eyes could be detected by ERG 3 months after injection in all groups. Changes observed in in vivo imaging such as OCT and FAF disappeared after 3 months in almost all cases., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: To assess comfort and procedural facility using a 25-gauge trocar cannula as a port to diagnose and treat acute endophthalmitis compared with a standard vitreous tap and injection technique., Methods: Eighteen consecutive patients with acute endophthalmitis were randomized into two treatment arms: 1) Standard vitreous tap and injection technique, and 2) A technique where a valved 25-gauge trocar cannula is inserted through the pars plana as done in sutureless vitrectomy surgery and subsequent vitreous sampling and injections are performed through the port. A standardized anesthetic protocol was used and subjects were masked to the technique performed. Primary outcomes measured were patient comfort using a Wong-Baker pain scale and standardized physician ease-of-use scoring scale. Secondary outcomes included vitreous sampling success rate and volume of vitreous sample., Results: No significant differences were found when comparing patient comfort (P = 0.340), physician ease-of-use scores (P = 0.796), vitreous sample volume (P = 0.149), successful vitreous taps (P = 0.620), and microbiologic yield (P = 1.000) between treatment arms. There were no adverse events., Conclusion: The 25-gauge trocar technique provides a safe, well-tolerated, and equally effective alternative to the standard vitreous tap and injection technique for delivery of intravitreal antibiotics, and procuring of vitreous sample, requiring a single sharp penetration.

Purpose: The Rapid Access Vitreal Injection (RAVI) guide combines the function of an eyelid speculum and measuring caliper into a single instrument for assisting intravitreal injections. This study clinically evaluated the RAVI guide with respect to patient acceptance, complication rates, and operative goals., Methods: A prospective study was performed on 54 patients undergoing intravitreal injections using the RAVI guide (n = 32) or the speculum/caliper (n = 22). Device-related pain was assessed using the Wong-Baker scoring system, scaled from 0 (no pain) to 10 (agonizing pain)., Results: Mean device-related pain score did not differ significantly between the 2 groups, with scores of 0.6 and 0.7 for the RAVI guide and speculum groups, respectively. The rate of significant pain (score of ≥2) was twice as high in the speculum group (7 of 22, 32%) compared with the RAVI guide group (5 of 32, 16%), but this difference was not statistically significant (P = 0.19, Fisher's exact test). Operative goals of avoiding needle touch to lashes/lids and guiding needle insertion to the intended site were achieved in all patients., Conclusion: The RAVI guide appeared equivalent to the eyelid speculum in achieving operative goals, with similarly low pain scores. It has the potential for facilitating efficient, accurate, and safe intravitreal injections.