Retinal Vascular Permeability in Diabetic Subjects without Retinopathy Compared with Mild Diabetic Retinopathy and Healthy Controls.

Objective: To investigate retinal vascular permeability mapping as a potential biomarker for diabetic retinopathy in subjects with diabetes with no signs of retinopathy and with mild nonproliferative retinopathy.

Design: This is a case-control study.

Subjects: Participants included 7 healthy controls, 22 subjects with diabetes mellitus and no clinical signs of retinopathy (DMnoDR), and 7 subjects with mild nonproliferative diabetic retinopathy (NPDR).

Fluorescein videoangiography data analysis protocol for mapping retinal vascular permeability in humans.

Fluorescein video angiographies (FVAs) are a diagnostic tool for eye diseases, such as diabetic retinopathy (DR). Currently, kinetic tracer model methods based on indicator-dilutions theory use FVAs to extract biomarkers (e.g.

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 disregards frequency fidelity in image reconstruction, leading to a frequency bias.

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.

Biodegradable Microspheres and Hydrogel Drug Delivery System of Tumor Necrosis Factor (TNF) Inhibitor and Growth Differentiation Factor 5 (GDF5) Reduces Disk Inflammation in the Rabbit Model.

Study Design: Preclinical study.

Objective: Develop and test a drug delivery system (DDS) composed of anti-inflammatories and growth factors in the rabbit disk injury model.

Summary Of Background Data: Biological therapies that inhibit inflammation or enhance cell proliferation can alter intervertebral disk (IVD) homeostasis to favor regeneration.

Simultaneous Release of Aflibercept and Dexamethasone from an Ocular Drug Delivery System.

Purpose: Intravitreal injections of anti-vascular endothelial growth factors (anti-VEGF) are the current standard of care for patients with choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). There is a growing subset of patients that does not respond to anti-VEGF monotherapy treatment. Some patients, however, do respond to combination therapy of corticosteroids and anti-VEGF.

Optimizing the protocol for retinal vascular permeability mapping from fluorescein videoangiography data.

An intact blood-retinal barrier is critical to maintaining the function of the retina. Many diseases of the eye have been directly associated with impairment in vascular permeability, and methods to measure vascular permeability could offer a window into early detection of disease; however, there exist no direct measures of vascular permeability that have be translated to the clinic. This work details a complete clinical workflow to quantify vascular permeability and volumetric blood flow from fluorescein videoangiography data, with validation through realistic simulations.

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.

Treatment Efficacy and Biocompatibility of a Biodegradable Aflibercept-Loaded Microsphere-Hydrogel Drug Delivery System.

Purpose: To evaluate the in vivo treatment efficacy and biocompatibility of a biodegradable aflibercept-loaded microsphere-hydrogel drug delivery system (DDS) in a laser-induced choroidal neovascularization (CNV) rat model.

Methods: Two weeks after CNV induction, animals were randomly assigned into four experimental groups: (1) no treatment, (2) single intravitreal (IVT) injection of blank DDS, (3) bimonthly bolus IVT aflibercept injections, and (4) single IVT injection of aflibercept-DDS. CNV lesion sizes were monitored longitudinally using fluorescence angiography and multi-Otsu thresholding for 6 months.

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

Purpose: To evaluate the safety and tolerability of a microsphere thermo-responsive hydrogel drug delivery system (DDS) loaded with aflibercept in a nonhuman primate model.

Methods: A 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.

Advances in ocular drug delivery systems.

Recent advances in pharmacological agents have led to successful treatment of a variety of retinal diseases such as neovascular age-related macular degeneration (AMD), diabetic macular oedema (DMO), and retinal vascular occlusions (RVO). These treatments often require repeated drug injections for an extended period of time. To reduce these repeated treatment burdens, minimally invasive drug delivery systems are needed.

Controlled Release of Vancomycin From a Thermoresponsive Hydrogel System for the Prophylactic Treatment of Postoperative Acute Endophthalmitis.

Purpose: To investigate the efficacy of a poly(ethylene glycol) diacrylate and poly(N-isopropylacrylamide) based thermo-responsive hydrogel drug delivery system (DDS) to deliver prophylactic vancomycin (VAN) following ocular surgery.

Methods: VAN was encapsulated in a hydrogel DDS and characterized in terms of initial burst, release kinetics, bioactivity, and cytotoxicity. Long-Evans rats received an intravitreal injection of to produce acute endophthalmitis in four experimental groups.

Characterization of Biodegradable Microsphere-Hydrogel Ocular Drug Delivery System for Controlled and Extended Release of Ranibizumab.

Purpose: To characterize a biodegradable microsphere-hydrogel drug delivery system (DDS) for controlled and extended release of ranibizumab.

Methods: The degradable microsphere-hydrogel DDSs were fabricated by suspending ranibizumab-loaded or blank poly(lactic-glycolic acid) microspheres within a poly(ethylene glycol)--(L-lactic-acid) diacrylate/N-isopropylacrylamide (PEG-PLLA-DA/NIPAAm) hydrogel. The thermal responsive behavior of various DDS formulations was characterized in terms of volume phase transition temperature (VPTT) and swelling ratios changes from 22°C to 42°C.

Biodegradable Microsphere-Hydrogel Ocular Drug Delivery System for Controlled and Extended Release of Bioactive Aflibercept In Vitro.

Purpose: Current standard of care for neovascular eye diseases require repeated intravitreal bolus injections of anti-vascular endothelial growth factors (anti-VEGFs). The purpose of this study was to validate a degradable microsphere-thermoresponsive hydrogel drug delivery system (DDS) capable of releasing bioactive aflibercept in a controlled and extended manner for 6 months.

Materials And Methods: The DDS was fabricated by suspending aflibercept-loaded poly(lactic-co-glycolic acid) microspheres within a biodegradable poly(ethylene glycol)-co-(l-lactic acid) diacrylate/N-isopropylacrylamide (PEG-PLLA-DA/NIPAAm) thermoresponsive hydrogel.

In Vivo Efficacy of an Injectable Microsphere-Hydrogel Ocular Drug Delivery System.

Purpose: Demonstrate in vivo that controlled and extended release of a low dose of anti-vascular endothelial growth factor (anti-VEGF) from a microsphere-hydrogel drug delivery system (DDS) has a therapeutic effect in a laser-induced rat model of choroidal neovascularization (CNV).

Methods: Anti-VEGF (ranibizumab or aflibercept) was loaded into poly(lactic-co-glycolic acid) microspheres that were then suspended within an injectable poly(N-isopropylacrylamide)-based thermo-responsive hydrogel DDS.The DDS was shown previously to release bioactive anti-VEGF for ~200 days.

Extended ocular drug delivery systems for the anterior and posterior segments: biomaterial options and applications.

The development of new therapies for treating various eye conditions has led to a demand for extended release delivery systems, which would lessen the need for frequent application while still achieving therapeutic drug levels in the target tissues. Areas covered: Following an overview of the different ocular drug delivery modalities, this article surveys the biomaterials used to develop sustained release drug delivery systems. Microspheres, nanospheres, liposomes, hydrogels, and composite systems are discussed in terms of their primary materials.

Controlled and Extended In Vitro Release of Bioactive Anti-Vascular Endothelial Growth Factors from a Microsphere-Hydrogel Drug Delivery System.

Purpose: To demonstrate controlled and extended release of bioactive anti-vascular endothelial growth factor (VEGF) agents (ranibizumab or aflibercept) from an injectable microsphere-hydrogel drug delivery system (DDS).

Methods: Anti-VEGF agents were radiolabeled with iodine-125 and loaded into poly(lactic-co-glycolic acid) (PLGA) 75:25 microspheres using a modified double-emulsion, solvent evaporation technique. Microspheres were then suspended in an injectable poly(N-isopropylacrylamide)-based thermo-responsive hydrogel to create a microsphere-hydrogel DDS.

Thermo-Responsive Hydrogels for Ocular Drug Delivery.

Hydrogel as an ocular drug delivery platform holds great potential. Hydrogels are three-dimensional, hydrophilic, polymeric networks capable of absorbing large amounts of water or biological fluids. They have the ability to swell in an aqueous solvent system, holding solvents within a cross-linked gel system for potential sustained delivery.

Quantitative retinal blood flow mapping from fluorescein videoangiography using tracer kinetic modeling.

Abnormal retinal blood flow (RBF) has been associated with numerous retinal pathologies, yet existing methods for measuring RBF predominantly provide only relative measures of blood flow and are unable to quantify volumetric blood flow, which could allow direct patient to patient comparison. This work presents a methodology based on linear systems theory and an image-based arterial input function to quantitatively map volumetric blood flow from standard fluorescein videoangiography data, and is therefore directly translatable to the clinic. Application of the approach to fluorescein retinal videoangiography in rats (4 control, 4 diabetic) demonstrated significantly higher RBF in 4-5 week diabetic rats as expected from the literature.

Controlled and Extended Release of a Model Protein from a Microsphere-Hydrogel Drug Delivery System.

In extended ocular drug delivery applications, it is necessary to exert control over the release characteristics of the drug. Design considerations must be made to limit the initial burst (IB) and ensure complete release of drug from the drug delivery system (DDS). In this study, ovalbumin was used as a model protein to explore the effects on release of polymer formulation and fabrication technique in poly(lactic-co-glycolic acid) (PLGA) microspheres.

Inverse relationship between the intraretinal concentration of bioavailable nitric oxide and blood glucose in early experimental diabetic retinopathy.

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.

Advances in ocular drug delivery: emphasis on the posterior segment.

Introduction: Recent advances in pharmacological therapies to treat ocular diseases such as glaucoma, age-related macular degeneration, diabetic macular edema and retinal vascular occlusions have greatly improved the prognosis for these diseases. Due to these advances in pharmacological therapy, there is a great deal of interest in minimally invasive delivery methods, which has generated rapid developments in the field of ocular drug delivery.

Areas Covered: This review will summarize currently available and recent developments for ocular drug delivery to both the anterior and posterior segments.

Objective area measurement technique for choroidal neovascularization from fluorescein angiography.

The purpose of this study was to develop a non-biased method of quantitatively measuring choroidal neovascularization (CNV) areas based on late-phase fluorescein angiography (FA) images. Experimental CNV was induced in Long Evans rats by laser disruption of the Bruch's membrane. FA was performed weekly for 5weeks.

Dual electroretinogram/nitric oxide carbon fiber microelectrode for direct measurement of nitric oxide in the in vivo retina.

Nitric oxide (NO) plays an important physiological role in normal and pathological retinas. Intraretinal NO concentrations have not been directly measured due to lack of NO electrodes capable of determining their location in the retina. The microelectrodes described here allow recording of the intraretinal electroretinogram (ERG) and NO concentration from the same location, with ERGs used to determine retinal depth.

The effect of glutathione as chain transfer agent in PNIPAAm-based thermo-responsive hydrogels for controlled release of proteins.

Purpose: To control degradation and protein release using thermo-responsive hydrogels for localized delivery of anti-angiogenic proteins.

Methods: Thermo-responsive hydrogels derived from N-isopropylacrylamide (NIPAAm) and crosslinked with poly(ethylene glycol)-co-(L-lactic acid) diacrylate (Acry-PLLA-b-PEG-b-PLLA-Acry) were synthesized via free radical polymerization in the presence of glutathione, a chain transfer agent (CTA) added to modulate their degradation and release properties. Immunoglobulin G (IgG) and the recombinant proteins Avastin® and Lucentis® were encapsulated in these hydrogels and their release was studied.