Biochemistry and Molecular Biology Inverse Relationship Between the Intraretinal Concentration of Bioavailable Nitric Oxide and Blood Glucose in Early Experimental Diabetic Retinopathy

Citation: Guthrie MJ, Osswald CR, Kang-Mieler JJ. Inverse relationship between the intraretinal concentration of bioavailable nitric oxide and blood glucose in early experimental diabetic retinopathy. Invest Ophthalmol Vis Sci. 2015;56:37-44. DOI:10. 1167/iovs.14-15777 PURPOSE. To directly measure in vivo retinal nitric oxide (NO) concentration in experimental early diabetic retinopathy and correlate measurements with blood glucose to determine how intraretinal NO changes with severity of diabetes. METHODS. Long-Evans rats were made diabetic with streptozotocin (STZ). Three weeks post STZ injection, intraretinal NO concentration profiles were recorded using a dual NO/ electroretinogram microelectrode. Diabetic profiles were compared with profiles from healthy controls, healthy rats injected with the NO synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME), and healthy rats that received acute glucose injections (''acute hyperglycemia''). The NO values at the retina/RPE boundary (100% retinal depth) and retinal surface (0% depth) were analyzed for correlation with blood glucose. RESULTS. The average NO concentrations in the outer retina, inner retina, and vitreous humor of mild diabetic rats (250-400 mg/dL) were significantly higher than controls by 73%, 47%, and 70%, respectively. The average NO concentrations in the outer retina, inner retina, and vitreous humor of severe diabetic rats (500-600 mg/dL) were lower than controls, with NO at 41%, 36%, and 36% of controls, respectively, similar to L-NAME-treated eyes (38%, 36%, 20% of control). The NO levels in moderate diabetic rats (400-500 mg/dL) and acute hyperglycemia rats were similar to controls. The NO was significantly and inversely correlated with blood glucose for diabetic rats at 100% depth (R ¼ À0.91) and 0% depth (R ¼ À0.79) but not for acute hyperglycemia rats. CONCLUSIONS. The higher-than-control level of NO in mild diabetic rats and lower-than-control level in severe diabetic rats show that severity of diabetes is an important factor when measuring the bioavailability of NO in diabetic retinopathy

Frequency-aware optical coherence tomography image super-resolution via conditional generative adversarial neural network

Optical coherence tomography (OCT) has stimulated a wide range of medical image-based diagnosis and treatment in fields such as cardiology and ophthalmology. Such applications can be further facilitated by deep learning-based super-resolution technology, which improves the capability of resolving morphological structures. However, existing deep learning-based method only focuses on spatial distribution and disregard frequency fidelity in image reconstruction, leading to a frequency bias. To overcome this limitation, we propose a frequency-aware super-resolution framework that integrates three critical frequency-based modules (i.e., frequency transformation, frequency skip connection, and frequency alignment) and frequency-based loss function into a conditional generative adversarial network (cGAN). We conducted a large-scale quantitative study from an existing coronary OCT dataset to demonstrate the superiority of our proposed framework over existing deep learning frameworks. In addition, we confirmed the generalizability of our framework by applying it to fish corneal images and rat retinal images, demonstrating its capability to super-resolve morphological details in eye imaging.Comment: 13 pages, 7 figures, submitted to Biomedical Optics Express special issu

Decreased Circulation in the Feline Choriocapillaris Underlying Retinal Photocoagulation Lesions

Panretinal photocoagulation is used to treat diabetic retinopathy. Measurements with SLO and microspheres show that the choriocapillaris is locally damaged under lesions in the cat retina. This damage could limit the effectiveness of photocoagulation

Safety and Biocompatibility of Aflibercept-Loaded Microsphere Thermo-Responsive Hydrogel Drug Delivery System in a Nonhuman Primate Model.

PurposeTo evaluate the safety and tolerability of a microsphere thermo-responsive hydrogel drug delivery system (DDS) loaded with aflibercept in a nonhuman primate model.MethodsA sterile 50 µL of aflibercept-loaded microsphere thermo-responsive hydrogel-DDS (aflibercept-DDS) was injected intravitreally into the right eye of 10 healthy rhesus macaques. A complete ophthalmic examination, intraocular pressure (IOP) measurement, fundus photography, spectral-domain optical coherence tomography (SD-OCT), and electroretinogram were performed monthly for 6 months. One macaque was euthanized monthly, and the enucleated eyes were submitted for measurement of bioactive aflibercept concentrations. Four eyes were submitted for histopathology.ResultsInjected aflibercept-DDS was visualized in the vitreous until 6 months postinjection. No abnormalities were observed in the anterior segment, and IOP remained within normal range during the study period. A small number of cells were observed in the vitreous of some macaques, but otherwise the remainder of the posterior segment examination was normal. No significant changes in retinal architecture or function as assessed by SD-OCT and histology or full-field electroretinography, respectively, were observed. A mild, focal foreign body reaction around the injectate was observed with histology at 6 months postinjection. A mean of 2.1 ng/µL of aflibercept was measured in the vitreous.ConclusionsIntravitreally injected aflibercept-DDS achieved controlled, sustained release of aflibercept with no adverse effects for up to 6 months in the eyes of healthy rhesus macaques.Translational relevanceAflibercept-DDS may be a more effective method to deliver bioactive antivascular endothelial growth factor agents than current practice by reducing the frequency of intravitreal injections and providing controlled drug release

Compartmental and COMSOL Multiphysics 3D Modeling of Drug Diffusion to the Vitreous Following the Administration of a Sustained-Release Drug Delivery System

The purpose of this study was to examine antibiotic drug transport from a hydrogel drug delivery system (DDS) using a computational model and a 3D model of the eye. Hydrogel DDSs loaded with vancomycin (VAN) were synthesized and release behavior was characterized in vitro. Four different compartmental and four COMSOL models of the eye were developed to describe transport into the vitreous originating from a DDS placed topically, in the subconjunctiva, subretinally, and intravitreally. The concentration of the simulated DDS was assumed to be the initial concentration of the hydrogel DDS. The simulation was executed over 1500 and 100 h for the compartmental and COMSOL models, respectively. Based on the MATLAB model, topical, subconjunctival, subretinal and vitreous administration took most (~500 h to least (0 h) amount of time to reach peak concentrations in the vitreous, respectively. All routes successfully achieved therapeutic levels of drug (0.007 mg/mL) in the vitreous. These models predict the relative build-up of drug in the vitreous following DDS administration in four different points of origin in the eye. Our model may eventually be used to explore the minimum loading dose of drug required in our DDS leading to reduced drug use and waste