Search

Proliferative vitreoretinopathy (PVR) is a significant threat for vision recovery from retinal detachment or ocular trauma. Currently, no approved pharmacological intervention to prevent PVR. Daunorubicin (DNR) and dexamethasone (DEX) were sequentially loaded into oxidized porous silicon (pSiO 2 ) particles by covalent conjugation. The DNR + DEX-loaded particles, and control particles loaded with DNR only and DEX only were incubated with RPE-populated collagen for daily gel surface quantitation. Toxicity was monitored by ophthalmic examinations and histological evaluation 21 days after injection. At 3rd week following intravitreal injection, a localized retinal detachment (RD) was created by subretinal injection of Healon in all pretreated eyes in addition to 3 non-interventional control eyes. 10 µg of bromodeoxyuridine (BrdU) was injected into the vitreous 4 h before sacrifice on day 3 after RD induction. Retinal sections were stained for glial fibrillary green protein (GFAP) and BrdU to identify activated glial cells and retinal cell proliferation. The studies demonstrated that all three pSiO 2 particle types were well tolerated in vivo. DNR alone and DNR + DEX combination formulations demonstrated equally strong suppression on gel contraction (least square mean area of the gel: control = 1.71 vs. 30DNR = 1.85 or 30/40Dual = 1.83, p  < .05). Eyes pretreated with pSiO 2 -DNR + DEX exhibited the least GFAP activation (least square mean intensity mm -2 : Dual = 4.03, DNR = 7.76, Dex = 16.23, control = 29.11, p  < .05) and BrdU expression (Mean number of BrdU positive cells per mm of retina: Dual = 2.77, DNR = 4.58, Dex = 4.01, control = 6.16, p  < .05). The synergistic effect of a sustained release pSiO 2 -DNR/DEX showed promise for the prevention of PVR development while reducing the necessary therapeutic concentration of each drug.

Purpose: To estimate the diffusion coefficients of an IgG antibody (150 kDa) and its antigen-binding fragment (Fab; 50 kDa) in the neural retina (D ret ) and the combined retinal pigment epithelium-choroid (D RPE-cho ) with a 3-dimensional (3D) ocular pharmacokinetic (PK) model of the rabbit eye., Methods: Vitreous, retina, and aqueous humor concentrations of IgG and Fab after intravitreal injection in rabbits were taken from Gadkar et al. (2015). A least-squares method was used to estimate D ret and D RPE-cho with the 3D finite element model where mass transport was defined with diffusion and convection. Different intraocular pressures (IOP), initial distribution volumes (V init ), and neural retina/vitreous partition coefficients (K ret/vit ) were tested. Sensitivity analysis was performed for the final model., Results: With the final IgG model (IOP 10.1 Torr, V init 400 μl, K ret/vit 0.5), the estimated D ret and D RPE-cho were 36.8 × 10 -9 cm 2 s -1 and 4.11 × 10 -9 cm 2 s -1 , respectively, and 76% of the dose was eliminated via the anterior chamber. Modeling of Fab revealed that a physiological model parameter "aqueous humor formation rate" sets constraints that need to be considered in the parameter estimation., Conclusions: This study extends the use of 3D ocular PK models for parameter estimation using simultaneously macromolecule concentrations in three ocular tissues.

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.)

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.)

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.

Many long-acting delivery strategies for ocular indications rely on pH- and/or temperature-driven release of the therapeutic agent and degradation of the drug carrier. Yet, these physiological parameters are poorly characterized in ocular animal models. These strategies aim at reducing the frequency of dosing, which is of particular interest for the treatment of chronic disorders affecting the posterior segment of the eye, such as macular degeneration that warrants monthly or every other month intravitreal injections. We used anesthetized white New Zealand rabbits, Yucatan mini pigs, and cynomolgus monkeys to characterize pH and temperature in several vitreous locations and the central aqueous location. We also established post mortem pH changes in the vitreous. Our data showed regional and species differences, which need to be factored into strategies for developing biodegradable long-acting delivery systems.

Delivery of therapeutic agents to posterior segment of the eyes is challenging due to the anatomy and physiology of ocular barriers and thus long-acting implantable formulations are much desired. In this study, a thermogelling system composed of two poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymers was developed as an injectable matrix for intravitreal drug delivery. The thermogel was prepared by mixing a sol and a precipitate of PLGA-PEG-PLGA triblock copolymers with different block ratios, among which a hydrophobic glucocorticoid, dexamethasone (DEX), was incorporated. The DEX-loaded thermogel was a low-viscous liquid at low temperature and formed a non-flowing gel at body temperature. The in vitro release rate of DEX from the thermogel could be conveniently modulated by varying the mixing ratio of the two copolymers. The long-lasting intraocular residence of the thermogel was demonstrated by intravitreal injection of a fluorescence-labeled thermogel to rabbits. Compared with a DEX suspension, the intravitreal retention time of DEX increased from a dozen hours to over 1week when being loaded in the thermogel. Additionally, intravitreal administration of the thermogel did not impair the morphology of retina and cornea. This study reveals that the injectable PLGA-PEG-PLGA thermogel is a biocompatible carrier for sustained delivery of bioactive agents into the eyes, and provides an alternative approach for treatment of posterior segment diseases., (Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Purpose: The perfect intravitreal injection delivers an exact amount of medication with the least risk to vision and the eye. We examined 2 different methods of intravitreal injection to determine if an angled transscleral entry for intravitreal injection results in less egress of intravitreal contents, including medication., Methods: In a crossover controlled trial at an outpatient clinical facility within a major ophthalmology referral center, we treated 10 patients. The surgical technique involved injecting 0.05 mL of bevacizumab injected in one eye by both an orthogonal (straight in) and oblique (angled) technique. The intraocular pressure (IOP) was measured immediately before and after each monthly injection., Results: Orthogonal injections raised the IOP significantly less (mean 24.6 mm Hg or 126%) than oblique injections (29.6 mm Hg or 152%) (p = 0.045). There were no reported differences in injection-related pain or adverse effects between the techniques., Conclusions: Oblique or angled injections caused a larger IOP rise than straight or orthogonal injections. This finding suggests that oblique injections are self-sealing, deliver a higher dose of medication, or prevent vitreous reflux as well as close a potential portal of entry for pathogens.

There still is an unmet need for a safe and sustained intravitreal drug delivery system. In this study we are proposing and characterizing a micelle based, clear-media intravitreal drug delivery system using the lipid derivatized nucleoside analog, hexadecyloxypropyl-cidofovir (HDP-CDV, CMX 001). HDP-CDV forms micelles in water and in vitreous supernatant with the critical micelle concentration of 19 μg/mL and 9 μg/mL, respectively at 37 °C. The formed micelles had the average size of 274.7 nm and the Zeta potential of -47.1 mV. Drug release study in the excised rabbit vitreous showed a sustained release profile with a half-life of 2.7 days. The micelle formulation of HDP-CDV demonstrated a good safety profile in two animal species (rabbit and guinea pig) following intravitreal injection. The sustained efficacy was tested in a pretreatment study design and the drug potency was tested in an ongoing herpes simplex virus (HSV-1) retinitis model. The pretreatment studies using single intravitreal injection and later HSV-1 infection revealed at least 9 weeks of vitreous presence and therapeutic level of HDP-CDV, with 71% eyes protection from infection. The treatment study demonstrated that intravitreal administration halted active HSV-1 retinitis in 80% of the infected eyes while cidofovir (CDV) treatment failed to suppress active HSV-1 retinitis. In summary, lipid derivatized nucleoside analogs can be formulated as a micelle intravitreal injection and provides a sustained drug release in vitreous for chronic retinal diseases., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Purpose: To review evidence and provide updated guidelines on intravitreal (IVT) injection technique and monitoring., Methods: A review of the published literature on IVT injection from 2004 to 2014 formed the basis for round table deliberations by an expert panel of ophthalmologists., Results: The dramatic increase in the number of IVT injections has been accompanied by a comparable increase in evidence surrounding IVT practice patterns and techniques. The expert panel identified a number of areas that have evolved since publication of the original IVT injection guidelines in 2004, the most notable of which were a lack of evidence to support the routine use of pre-, peri-, and postinjection antibiotics to reduce the risk of endophthalmitis, and the role of aerosolized droplets containing oral contaminants from the patient and/or providers as a potential source of infection. The panel emphasized the continued importance of applying povidone-iodine to and avoiding eyelid contact with the intended injection site and needle., Conclusion: Updated guidelines on IVT injection technique and monitoring are proposed based on a review of published literature and expert panel deliberations.

Purpose: This study evaluated the vitreous pharmacokinetics and vitreous bioavailability of memantine following posterior-subtenon administration (PST) compared to intravitreal (INT) and intravenous routes (INV) in rabbits., Methods: Vitreous pharmacokinetic analysis was performed on female New Zealand (NZ) albino rabbits after PST, INT, and INV administration and calculating the pharmacokinetic parameters that describe memantine vitreous distribution. The vitreous bioavailability (F) and the relative vitreous bioavailability of memantine was estimated after posterior-subtenon administration (Frel (pst/int)) and after intravenous route (Frel (inv/int)) compared with intravitreal administration. Relative vitreous bioavailability of memantine was also estimated following PST administration compared with vitreous concentrations after intravenous administration (Frel (pst/inv))., Results: Memantine kinetics in the vitreous of NZ albino rabbits after PST administration can be explained by a one-compartment model, which was characterized by a fast absorption process, and a short terminal half-life. Vitreous pharmacokinetics following INV administration was also characterized by a fast absorption process, a terminal half-life significantly longer than the subtenon route, and low area under the curve values. High vitreous bioavailability after PST was observed, and the relative vitreous bioavailability of memantine following PST administration (0.53%) was greater than for intravenous administration (0.02%)., Conclusions: Our results suggest that memantine reaches the vitreous after PST administration by local diffusion. These data also show that local diffusion of the drug is responsible for greater vitreous availability of memantine following PST administration compared with INV administration.

Intravitreal injection is a common procedure performed by ophthalmologists. It is a quick and targeted treatment for a number of ophthalmic conditions. Despite this, the potential to cause serious complications and patient discomfort cannot be ignored. This article presents the level of evidence in the scientific literature supporting common practices such as location of the procedure, anaesthetic choice, sterile procedure techniques, comparison of some common pharmaceutical agents and the use of antibiotics., (© 2012 The Authors. Clinical and Experimental Ophthalmology © 2012 Royal Australian and New Zealand College of Ophthalmologists.)

Purpose: We recently demonstrated that direct subretinal (SR) injection of adeno-associated virus (AAV) type 8 (AAV8) into photoreceptor cells and retinal pigment epithelium (RPE) is a highly efficient model of gene delivery. The current study compared transduction efficiency and expression patterns associated with various routes of vector administration., Method: The efficacy of intravitreal (VT), SR and subconjunctival (SC) injections for delivery of AAV8-derived vectors, i.e. those expressing luciferase (Luc) and enhanced green fluorescent protein (GFP) - AAV8/Luc and AAV8/GFP, respectively - were compared in an animal (mouse) model (n = 8 mice/group). Transduction efficiency and expression patterns were examined at post-injection weeks 1 and 2, and months 1, 3, 6 and 12 via in vivo imaging., Results: One year after AAV injection, AAV8/Luc-treated mice exhibited stable and sustained high expression of vector in the VT and SR groups, but not in the SC group (VT:SR:SC = 3,218:2,923:115; 1 × 10(5 )photons/s). Histological analysis showed that GFP expression was observed in the inner retina of VT group mice, and in photoreceptor cells and RPE of SR group mice, whereas no GFP expression was noted in the SC group. Electroretinography (ERG) revealed adverse effects following SR delivery., Conclusions: Results suggest that both SR and VT injections of AAV8 vectors are useful routes for administering ocular gene therapy, and stress the importance of selecting an appropriate administration route, i.e. one that targets specific cells, for treating ocular disorders.

Purpose: To compare the effects of straight, oblique, and double-plane tunnel scleral intravitreal injection techniques, on short-term intraocular pressure (IOP) changes, occurrence of vitreous reflux (VR), and/or other complications., Methods: A total of 105 patients were included in this prospective study. Patients were assigned randomly to one of the straight injection group (SI; n=35), oblique injection group (OI; n=35), or double-plane tunnel injection group (DPTI; n=35). The occurrence of VR and preinjection and postinjection IOP at 2 and 6 h were compared between groups, and complications were assessed., Results: The mean patient age was 71.1±6.6 years (range 58 to 86 years; 50 women and 55 men). In the SI, OI, and DPTI groups, VR occurred in 18 (51.4%), 12 (34.3%), and 6 patients (17.1%), respectively. Mean preinjection IOPs were 15.4, 14.8, and 15.6 mmHg, and changed to 17.3, 18.0, and 20.0 mmHg at the second hour, and 15.7, 16.2, and 16.1 mmHg at the sixth hour, respectively. No significant differences among the groups were found in terms of complications such as transient mild uveitis or subconjunctival hemorrhage., Conclusion: Double-plane tunnel injection prevents VR from the injection site and has no additional complications than other techniques.

Background: The preservation of globe integrity has always been a major concern during the treatment of retinoblastoma for fear of extraocular or metastatic spread. Intravitreal chemotherapy has been attempted as a desperate salvage therapy only for eyes with refractory retinoblastoma. Published data on the safety and efficacy of this route are, however, limited., Methods: A modified technique of intravitreal injection in eyes with retinoblastoma is described. All children with retinoblastoma who received one or more intravitreal injections using this technique were retrospectively reviewed concerning ocular complications of the injection procedure as well as clinical or histopathological evidence of tumour spread., Results: 30 eyes of 30 children with retinoblastoma received a total of 135 intravitreal injections, with a median follw-up duration of 13.5 months. No extraocular spread was seen on clinical follow-up in any patients and there was no tumour contamination of the retrieved entry sites histopathologically analysed among the five enucleated eyes. No significant ocular side effects were observed except transient localised vitreous haemorrhage (3/135)., Conclusion: This technique is potentially safe and effective at a low cost and may play a promising role, especially in the treatment of recurrent and/or resistant vitreous disease in retinoblastoma, as an alternative to enucleation and/or external beam radiotherapy. However, this treatment should not replace the primary standard of care of retinoblastoma and should not be considered in group E eyes. Its application should be approved by an ophthalmological-oncological team and it should be performed by an experienced eye surgeon in a tertiary referral centre after careful selection of a tumour-free injection site.

Purpose: To determine whether bevacizumab and ranibizumab remain confined within the vitreous cavity after intravitreal injection and to determine the pharmacokinetic properties of these agents within the vitreous cavity., Methods: Radiolabeling with I-124 was completed using a modified Iodogen method. After testing for radiochemical purity, three anesthetized Dutch-belted rabbits underwent intravitreal injection with I-124 bevacizumab, and three underwent it with I-124 ranibizumab. All rabbits were imaged with a Micro PET-CT scanner on days 0, 2, 5, 7, 14, 21, 28, and 35., Results: The intravitreally placed radiolabeled agents were found to be contained within the vitreous cavity for the duration of the study with no extravasation into the central nervous system or elsewhere. I-124 bevacizumab was detectable until day 28, whereas I-124 ranibizumab was detectable until day 21. The kinetic model appears to represent a two-compartment model, and the average retention times for bevacizumab and ranibizumab after correction for radioactive decay were found to be 4.2 days and 2.8 days, respectively., Conclusions: There was no significant escape of bevacizumab and ranibizumab from the vitreous cavity after intravitreal injection. After correction for radioactive decay, both agents remained detectable until 28 and 21 days, respectively, with retention properties that validated those methods reported in previous studies.