Bioceramic implant reduces intraocular VEGF levels.

Elevated intraocular levels of angiogenic cytokines such as vascular endothelial growth factor (VEGF) have been implicated the development of diabetic retinopathy. Over a decade of clinical evidence shows intravitreal injection of anti-VEGF agents is associated with decreased disease progression and preservation of vision. However, the treatment burden associated with monthly injections limits the effectiveness of existing anti-VEGF therapies. Current research has focused on sustained treatment paradigms such as longer acting drugs, drug delivery implants, and gene therapy. In this study, we tested a novel approach by dialyzing proteins from the vitreous using bioceramic implant composed of hydroxyapatite. Preliminary in vitro and in vivo studies demonstrate a high affinity and capacity for VEGF absorption. After three months implantation in New Zealand White Cross rabbits, the hydroxyapatite demonstrated good biocompatibility with no inflammation and normal retinal physiology and histology. These studies demonstrate that prolonged VEGF suppression intraocularly may be accomplished with a bioceramic implant.

Vitreous protein binding with nanopore dialysis membrane device.

Age-related macular degeneration (AMD) is one of the leading causes of blindness in the industrialized world, affecting over 8 million patients in the United State alone. While the wet (exudative) form of the disease is treated with intraocular injections, there are currently no approved therapies available for the dry (non-exudative) form of the disease which often affects both eyes in patients with AMD. Current research has focused on developing drugs that can be injected into the eye, but the treatment burden associated with monthly injections limits the effectiveness of this approach. Hence, there is a pressing need for a long-term therapeutic solution for patients suffering from this blinding disease. We detail a novel implantable intraocular device, which adsorbs and traps complement factors associated with AMD. In this study, we tested a novel approach by dialyzing proteins from the vitreous using biocompatible implants composed of a nanopore polyacrylonitrile polymer membrane. Preliminary in vitro and in vivo studies demonstrate a high affinity and capacity for complement protein absorption. After a three-month implantation in New Zealand White Cross rabbits, the implant demonstrated good biocompatibility with no inflammation and normal retinal physiology and histology. These studies demonstrate that prolonged CF suppression intraocularly may be accomplished with a nanopore polymer membrane.

INCREASED COMPLEMENT LEVELS IN HUMAN VITREOUS ASPIRATES OF PROLIFERATIVE DIABETIC RETINOPATHY AND RETINAL DETACHMENT EYES.

PURPOSE: To evaluate levels of complement factors in human vitreous of eyes with retinal detachments (RDs) and proliferative diabetic retinopathy (PDR) eyes. METHODS: Human vitreous samples were collected from eyes undergoing routine vitrectomy at the University of Colorado Health Eye Center (Aurora, CO). Complement factor D, component C5/C5a, and component C9 levels were measured using enzyme-linked immunosorbent assay and multiplex assays. Retinal detachment and PDR eyes were compared with controls, which were defined as eyes with macular holes or epiretinal membranes. RESULTS: The levels of complement factor D in PDR (mean = 2,110.0 ng/mL, P = 0.001) and RD (mean = 660.9 ng/mL, P = 0.03) eyes were statistically significantly higher than controls (mean = 290.5 ng/mL). The levels of complement component C9 were also more elevated in PDR (P = 0.004) compared with control but not in RD eyes. CONCLUSION: Elevated complement factors, particularly of the alternative pathway, were noted in PDR and RD eyes compared with controls. One potential explanation for this is that the oxidative stress in RD and PDR eyes leads to complement dysregulation and alternative complement upregulation.

COLORADO AGE-RELATED MACULAR DEGENERATION REGISTRY: Design and Clinical Risk Factors of the Cohort.

PURPOSE: To study new and existing risk factors related to age-related macular degeneration (AMD) phenotypes in a Colorado cohort. METHODS: Age-related macular degeneration was categorized into early, intermediate, or advanced forms. Controls (n = 180) were patients with cataract and no AMD. Demographic and clinical data were gathered by patient interview and verified by chart review. Image data were reviewed by vitreoretinal specialists. Statistical analysis included univariable and multivariate logistic regression analysis (P < 0.05). RESULTS: Among the 456 patients with AMD, 157 (34.4%), 80 (17.6%), and 219 (48.0%) had the early/intermediate, geographic atrophy, and neovascular forms of the disease, respectively. Adjusted for age, African-American race was associated with a reduced risk of early/intermediate (adjusted odds ratio [AOR] = 0.08, confidence interval [CI] = 0.01-0.67) and neovascular AMD (AOR = 0.15, CI = 0.03-0.72). A family history of AMD was a risk factor for early/intermediate (AOR = 4.08, CI = 2.30-7.25), geographic atrophy (AOR = 8.62, CI = 3.77-19.7), and neovascular AMD (AOR = 3.76, CI = 2.16-6.56). A history of asthma was related to the early/intermediate form of AMD (AOR = 2.34, CI = 1.22-4.46). CONCLUSION: Studying AMD in specific populations may reveal novel risk factors such as our finding of a relationship between asthma history and AMD.

Metabolomics Analysis of Human Vitreous in Diabetic Retinopathy and Rhegmatogenous Retinal Detachment.

The vitreous humor is a highly aqueous eye fluid interfacing with the retina and lens and providing shape. Its molecular composition provides a readout for the eye's physiological status. Changes in cellular metabolism underlie vitreoretinal pathologies, but despite routine surgical collection of vitreous, only limited reports of metabolism in the vitreous of human patients have been described. Vitreous samples from patients with rhegmatogenous retinal detachment ( n = 25) and proliferative diabetic retinopathy ( n = 9) were profiled along with control human vitreous samples ( n = 8) by untargeted mass-spectrometry-based metabolomics. Profound changes were observed in diabetic retinopathy vitreous, including altered glucose metabolism and activation of the pentose phosphate pathway, which provides reducing equivalents to counter oxidative stress. In addition, purine metabolism was altered in diabetic retinopathy, with decreased xanthine and elevated levels of related purines (inosine, hypoxanthine, urate, allantoate) generated in oxidant-producing reactions. In contrast, the vitreous metabolite profiles of retinal detachment patients were similar to controls. In total, our results suggest a rewiring of vitreous metabolism in diabetic retinopathy that underlies disease features such as oxidative stress and furthermore illustrates how the vitreous metabolic profile may be impacted by disease.

Real-time measurement of needle forces and acute pressure changes during intravitreal injections.

BACKGROUND: The purpose of this study was to use a physiological pressure transducer to measure real-time, continuous pressure changes in an ex vivo study model of porcine eyes to record the amount of force needed for scleral penetration and to measure acute intraocular pressure rise during intravitreal injections. METHODS: A pressure transducer was inserted into the anterior chamber of 30 fresh porcine eyes, and intraocular pressure was measured 2 s prior to intravitreal injection until 2 s after. A force transducer plate was used to insert various gauge needles into the vitreous cavity and the amount of force in Newtons (N) required for scleral penetration was recorded. RESULTS: For scleral perforation, 32- and 30-gauge needles required 0.44 N and 0.45 N, significantly less than larger gauge needles (P < 0.05). Similarly, 27- and 25-gauge needles required more force than smaller gauge needles but less than 19 gauge (P < 0.05). Intraocular pressure increased an average of 64.5 mmHg during intravitreal injection. Two seconds postinjection intraocular pressure readings showed a residual intraocular pressure increase of 11.1 mmHg from pre-injection baseline. CONCLUSION: Real-time continuous recordings of pressure reveal that an instantaneous intraocular pressure spike occurs during intravitreal injection and appears to be separate from the intraocular pressure spike that occurs during needle insertion. This pressure spike is transient and has not been captured by previous methods of intraocular pressure measurement, which rely on single time point measurements. The clinical significance of this brief intraocular pressure spike is unclear and warrants further investigation.

Progression of gyrate atrophy measured with ultra-wide-field imaging.

The study aims to determine the progression of gyrate atrophy by measuring the area growth of chorioretinal atrophic lesions using ultra-wide-field images (UWFI). A retrospective, observational, and comparative study was conducted and UWFI (200°) were obtained from two patients with gyrate atrophy at baseline and follow-up. Measurements of atrophy were obtained for three types of lesions: Solitary atrophic lesions (SAL), De novo solitary lesions (DNSL), and peripapillary atrophy (PPA). Comparison of baseline and follow-up was done using t tests. Two patients with gyrate atrophy were included. Patient 1 presented 16 SAL, 5 DNSL, and PPA measured for both eyes (BE). Overall area growth (OAG) for SAL (expressed in decimals) presented a mean of 3.41, σ 3.07. DNSL area for BE presented a mean of 1586.08 P (2), σ 1069.55. OAG for PPA presented a mean of 1.21, σ 0.17. Patient 2 presented 5 SAL, no DNSL, and PPA was measured for BE. OAG for SAL presented a mean of 1.58, σ 1.05 (range 1.02-3.47). OAG for PPA presented a mean of 1.05, σ 0.001. Gyrate atrophy progression can be determined by measuring the changes in area using UWFI.

A nanopore membrane regulator device for laser modulated flow after glaucoma surgery.

Glaucoma, the second most common cause of blindness in the world, is a multifactorial disease with several risk factors, of which intraocular pressure (IOP) is a primary contributing factor. Filtration surgery is one of the most effective means to significantly lower IOP compared to medical or laser treatments, and it is typically reserved for advanced disease. However, there are high rates of postoperative complications associated with the procedure, often from over- or under-filtration. To address these problems, the glaucoma drainage device regulator (GDDR) implant was developed to allow post-operative control of aqueous flow and IOP. The device, a tube with a nanopore membrane, is placed beneath the scleral flap. Postoperatively, the membrane surface can be ruptured with a laser to augment flow through the system. This feature allows adjustable control of aqueous flow and diminishes the risk of hypotony in the early postoperative period.

Red cell exchange transfusion halts progressive proliferative sickle cell retinopathy in a teenaged patient with hemoglobin SC disease.

A male with sickle SC disease presented at age 8 years with proliferative sickle cell retinopathy (PSCR) and bilateral vitreous hemorrhage which spontaneously resolved, then recurred at 13 years of age. Despite conventional therapy with repeated pan-retinal photocoagulation and pars plana vitrectomy, he developed progressive PSCR and recurrent vitreous hemorrhage over the next 30 months. We describe the successful use of chronic red cell exchange transfusion (RCE) to preserve his vision and stabilize the retinopathy.

Identification and biometry of horizontal extraocular muscle tendons using optical coherence tomography.

PURPOSE: To purpose if this study was to determine whether the horizontal rectus muscle tendons (HRMTs) can be observed using anterior segment optical coherence tomography (AS-OCT) and to determine the repeatability of its measurements. Also, this study aimed to observe and measure the different external ocular structures at the level of the horizontal rectus muscle (HRM) insertion. METHODS: This was a retrospective, observational, descriptive and comparative study. Images were obtained utilizing the RTVue 100 CAM system. Eyes were analyzed at the three and nine o'clock position. Scans were performed for three different locations: the limbus, the ciliary body and the equator. All scans were analyzed by two graders, separately and blinded. Measurements were performed for: HRMT length; HRM thickness; conjunctival epithelium thickness; conjunctiva and Tenon's capsule thickness; scleral thickness; and external ocular thickness. RESULTS: Results were obtained from twenty eyes of ten volunteers. The conjunctival epithelium thickness was 52.33 µm, the total conjunctiva/Tenon's capsule thickness was 313.54 µm, the medial rectus (MR) thickness was 136.63 µm and the lateral rectus (LR) thickness was 181.65 µm. The MR tendon length was 1,426.88 µm, the LR tendon length was 1,433.65 µm, the scleral thickness was 489.91 µm and the total external ocular structure thickness was 785.17 µm. Intra-observer reproducibility (intraclass correlation coefficient [ICC]) for tendon length was 0.993 for grader #1, 0.989 for grader #2; the muscle thickness ICC was 0.990 for grader #1 and 0.981 for grader #2. The inter-observer reproducibility ICC for tendon length was 0.557; the ICC for muscle thickness was 0.834. CONCLUSIONS: It is possible to visualize and measure HRMTs using AS-OCT. Measurements of the HRM, as well as the surrounding external ocular tissues, can be achieved.

Spectral domain optical coherence tomographic analysis of healthy retina in branch retinal vein occlusion and its response to antiangiogenic therapy.

PURPOSE: To propose a model that measures the effect of intravitreal bevacizumab (IVB) on relatively healthy retina. The purpose is to analyze the remote effect of a branch retinal vein occlusion in the healthy retina, to determine the response it may have to IVB, and to determine if IVB has an atrophic effect on the healthy retina. METHODS: Retrospective, longitudinal comparative analysis of patients with branch retinal vein occlusion treated with IVB. Eyes were divided into experimental (branch retinal vein occlusion eye) and control (contralateral eye) groups. Each eye was analyzed for thickness and area. Thickness measurements were performed for total retinal thickness, inner retina thickness, and outer retina thickness. Area was measured for photoreceptors, choroid, and total retina. RESULTS: Eighteen eyes of 9 patients. For thickness analysis, 1,050 scans were studied, and 126 measurements were performed on 42 scans for area analysis. No difference was observed for thickness, except for inner retina thickness. No difference was observed for area. No difference was observed when analyzing a cumulative exposure to IVB. CONCLUSION: There is no evidence to suggest an atrophic effect caused by IVB when analyzing thickness or area in this experiment. This model could be used to analyze the long-term safety of IVB in larger studies.

Current knowledge and trends in age-related macular degeneration: genetics, epidemiology, and prevention.

PURPOSE: To address the most dynamic and current issues concerning human genetics, risk factors, pharmacoeconomics, and prevention regarding age-related macular degeneration. METHODS: An online review of the database Pubmed and Ovid was performed, searching for the key words: age-related macular degeneration, AMD, pharmacoeconomics, risk factors, VEGF, prevention, genetics and their compound phrases. The search was limited to articles published since 1985 to date. All returned articles were carefully screened and their references were manually reviewed for additional relevant data. The webpage www.clinicaltrials.gov was also accessed in search of relevant research trials. RESULTS: A total of 366 articles were reviewed, including 64 additional articles extracted from the references and 25 webpages and online databases from different institutions. At the end, only 244 references were included in this review. CONCLUSION: Age-related macular degeneration is a complex multifactorial disease that has an uneven manifestation around the world but with one common denominator, it is increasing and spreading. The economic burden that this disease poses in developed nations will increase in the coming years. Effective preventive therapies need to be developed in the near future.

Bispecific VEGF-A and Angiopoietin-2 Antagonist RO-101 Preclinical Efficacy in Model of Neovascular Eye Disease.

Objective: To investigate preclinical data regarding the efficacy and biocompatibility of a bispecific protein, RO-101, with effects on VEGF-A and angiopoietin-2 (Ang-2) for use in retinal diseases. Design: Experimental study. Subjects: Brown Norway rats and New Zealand White Cross rabbits. Methods: Preclinical study data of RO-101 in terms of target-specific enzyme-linked immunosorbent assay binding affinity to VEGF-A and Ang-2, vitreous half-life, inhibition of target-receptor interaction, laser choroidal neovascular membrane animal model, human umbilical vein endothelial cell migration, and biocompatibility was obtained. Where applicable, study data were compared with other anti-VEGF agents. Main Outcome Measures: Binding affinity, half-life, biocompatibility, and efficacy of RO-101. Neovascularization prevention by RO-101. Results: RO-101 demonstrated a strong binding affinity for VEGF-A and Ang-2 and in vitro was able to inhibit binding to the receptor with higher affinity than faricimab. The half-life of RO-101 is comparable to or longer than current VEGF inhibitors used in retinal disease. RO-101 was found to be biocompatible with retinal tissue in Brown Norway rats. RO-101 was as effective or more effective than current anti-VEGF therapeutics in causing regression of neovascular growth in vivo. Conclusions: RO-101 is a promising candidate for use in retinal diseases. In preclinical models, RO-101 demonstrated similar or higher regression of neovascular growth to current anti-VEGF therapeutics with comparable or longer half-life. It also demonstrates a strong binding affinity for VEGF-A and Ang-2. It also was shown to be biocompatible with retinal tissue in animal studies, indicating potential compatibility for use in humans. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Current knowledge and trends in age-related macular degeneration: today's and future treatments.

PURPOSE: To address the most dynamic and current issues concerning today's treatment options and promising research efforts regarding treatment for age-related macular degeneration. This review is aimed to serve as a practical reference for more in-depth reviews on the subject. METHODS: An online review of the database PubMed and Ovid were performed, searching for the key words age-related macular degeneration, AMD, VEGF, treatment, PDT, steroids, bevacizumab, ranibizumab, VEGF-trap, radiation, combined therapy, as well as their compound phrases. The search was limited to articles published since 1985. All returned articles were carefully screened, and their references were manually reviewed for additional relevant data. The web page www.clinicaltrials.gov was also accessed in search of relevant research trials. RESULTS: A total of 363 articles were reviewed, including 64 additional articles extracted from the references. At the end, only 160 references were included in this review. CONCLUSION: Treatment for age-related macular degeneration is a very dynamic research field. While current treatments are mainly aimed at blocking vascular endothelial growth factor, future treatments seek to prevent vision loss because of scarring. Promising efforts have been made to address the dry form of the disease, which has lacked effective treatment.

Experimental measure of retinal impact force resulting from intraocular foreign body dropped onto retina through media of differing viscosity.

BACKGROUND: To evaluate and compare the perfluorocarbon liquid, silicone oil, and viscoelastic against standard saline, in their ability to dampen the impact force of a foreign body, dropped within the eye. In an experimental surgical model in where cohesive and adhesive forces of the substances are not enough to float heavy-than-water foreign bodies. METHODS: A model of ophthalmic surgery was constructed. A BB pellet was dropped from 24 mm onto a force transducer through four different fluids: balanced salt solution, perfluoro-n-octane, viscoelastic, and silicone oil. The impact energy (force) for each case was measured and recorded by the force transducer. The mean force of impact for each fluid was compared using the Student t-test. RESULTS: Silicone oil resulted in the lowest force of impact. Both silicone oil and viscoelastic dampened the impact an order of magnitude more than perfluoro-n-octane and balanced salt solution. CONCLUSIONS: Silicone oil and viscoelastic cushioned the force from a dropped BB. They may be useful adjuncts to prevent iatrogenic retinal injury during vitrectomy for intraocular foreign body removal.

Treatment of intractable posterior uveitis in pediatric patients with the fluocinolone acetonide intravitreal implant (Retisert).

PURPOSE: To evaluate the efficacy and safety of the fluocinolone acetonide intravitreal implant in pediatric patients with intractable noninfectious posterior uveitis. METHODS: A retrospective chart review was performed on all patients aged <18 years on whom a fluocinolone implant was used to treat intractable posterior uveitis at our institution. Conventional treatment with topical and systemic steroids and/or systemic steroid-sparing agents failed in all patients before proceeding with an implant. Each implant contained 0.59 mg of fluocinolone acetonide. Implants were placed in the inferonasal quadrant through a pars plana incision and sutured in place with 8-0 proline suture. Postoperatively, patients were followed for improvement in Snellen visual acuity, control of inflammation, and development of complications such as infection or uncontrolled intraocular pressure in the eyes. RESULTS: The study included six eyes of four patients. Mean age at implant placement was 9.2 years (range, 6-13 years). Four eyes were pseudophakic at the time of surgery; one eye had pars plana lensectomy at the time of surgery. Mean follow-up duration was 698 days (range, 376-1,189 days). Postoperative visual acuity improved by ≥3 lines in 3 eyes. Four eyes had postoperative intraocular spikes ≥30 mmHg, with 2 eyes having ≥40 mmHg. Two of these patients required glaucoma shunting procedures postoperatively for intraocular pressure control. Inflammation was well controlled postoperatively in all six eyes with all eyes successfully weaned off of topical steroids. The single phakic eye developed a visually significant cataract 18 months postoperatively requiring cataract extraction. There were no cases of postoperative infection. There were no postoperative complications of surgical technique including no instances of wound leakage or implant dislocation. CONCLUSION: The fluocinolone implant can be used effectively for control of posterior inflammation in pediatric patients. As in adults, concerns for development of cataract and secondary glaucoma remain. No other safety concerns were evident in this pilot study.

EFFICACY OF INTRAVITREAL AFLIBERCEPT INJECTIONS IN THE TREATMENT OF IDIOPATHIC RETINAL VASCULITIS, ANEURYSMS, AND NEURORETINITIS SYNDROME.

PURPOSE: To present a case of idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome that was successfully managed with serial intravitreal aflibercept injections. METHODS: Ophthalmic imaging and visual acuity were used to monitor disease state and track treatment methods to determine the most valuable combination of treatment medication and treatment interval. RESULTS: A 28-year-old woman with idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome status after panretinal photocoagulation of both eyes presented with bilateral cystoid macular edema. We demonstrate successful management of retinal cystoid macular edema associated with idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome using serial intravitreal aflibercept injections. CONCLUSION: Intravitreal aflibercept has a useful role in managing the potential retinal complications associated with idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome and provides further insights into treatment of the later stages of this rare disease.

Intravitreal infliximab and choroidal neovascularization in an animal model.

OBJECTIVE: To determine whether intravitreal infliximab can inhibit the growth of choroidal neovascularization (CNV) in an animal model of age-related macular degeneration. METHODS: Twenty-four brown Norway rats received 6 argon laser lesions of sufficient power to rupture the Bruch membrane in each eye. The right eye received a single intravitreal infliximab injection of 0.15 mg/mL, 1.5 mg/mL, or 15 mg/mL. The left eye received an injection of balanced saline solution. The animals were then euthanized at day 30, the eyes were enucleated, and the amount of CNV was quantified with digital analysis software. RESULTS: Intravitreal infliximab inhibited CNV growth in the rat laser-trauma model in a dose-response manner. In the 1.5-mg/mL group, there was an 11% reduction in CNV growth (P = .01). In the 15-mg/mL group, CNV growth was decreased by 68% (P < .001). CONCLUSIONS: Infliximab can inhibit CNV in a rat laser-trauma model, implicating its target cytokine tumor necrosis factor alpha in the angiogenic stimulus for CNV. Suppression of inflammatory cytokines may prove to be another therapeutic target in the treatment of exudative macular degeneration. Clinical Relevance This study demonstrates in a model of macular degeneration an antiangiogenic effect of intravitreal infliximab, which provides a rationale for future human studies.