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. An ideal therapy should maintain effective levels of drug for the intended duration of treatment following a single application, recognising that a significant number of months of therapy may be required. There are numerous approaches under investigation to improve treatment options. This review will highlight the advantages and limitations of selected drug delivery systems of novel biomaterial implants and depots. The main emphasis will be placed on less invasive, longer acting, sustained release formulations for the treatment of retinal disorders.

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-coglycolic acid) microspheres within a biodegradable poly(ethylene glycol)-co-(Llactic acid) diacrylate/N-isopropylacrylamide (PEG-PLLA-DA/NIPAAm) thermoresponsive hydrogel. Encapsulation efficiency of DDSs and in vitro release profiles were characterized by iodine-125 radiolabeled aflibercept. The degradation of hydrogel was determined by dry weight changes. The cytotoxicity from degraded DDS byproducts was investigated by quantifying cell viability using LIVE/DEAD® assay. In addition, dot blot and enzyme-linked immunosorbent assay were used to determine the bioactivity of released drug. Finally, morphology of microspheres and hydrogel were investigated by cryo-scanning electron microscopy before and after thermal transformation. Results:The microsphere-hydrogel DDS was capable of releasing bioactive aflibercept in a controlled and extended manner for 6 months. The amount and rate of aflibercept release can be controlled by both the cross-linker concentration and microspheres load amount. The initial burst (release within 24 h) was from 37.35 ± 4.92 to 74.56 ± 6.16 μg (2 and 3 mM hydrogel, each loaded with 10 and 20 mg/ml of microspheres, respectively), followed by controlled drug release of 0.07-0.15 μg/day. Higher PEG-PLLA-DA concentration (3 mM) degraded faster than the lower concentration (2 mM). No significant cytotoxicity from degraded DDS byproducts was found for all investigated time points. Bioactivity of released drug was maintained at therapeutic level over entire release period.

PurposeTo characterize a biodegradable microsphere-hydrogel drug delivery system (DDS) for controlled and extended release of ranibizumab.MethodsThe degradable microsphere-hydrogel DDSs were fabricated by suspending ranibizumab-loaded or blank poly(lactic-co-glycolic acid) microspheres within a poly(ethylene glycol)-co-(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. The mechanical properties were characterized using rheological methods. Degradability of hydrogels were also examined via wet weight loss. Finally, Iodine-125 was used to radiolabel ranibizumab for characterization of encapsulation efficiency and in vitro release.ResultsAll DDS formulations investigated were injectable through a 28-gauge needle at room temperature. The VPTT increased with increase of cross-linker concentration. The swelling ratios decreased as temperature increased and were not influenced by presence of microspheres. Rheology data confirmed that increase of cross-linker concentration and microsphere loading made DDS stiffer. Increase of degradable cross-linker concentration facilitated hydrogel in vitro degradation. Controlled release of ranibizumab were achieved for investigated DDS formulations for 6 months; and increased degradable cross-linker concentration produced faster and more complete release.ConclusionsThe biodegradable DDSs are suitable for sustained release of ranibizumab. Considering ease of injection, degradability and release of ranibizumab, DDS with 3 mM cross-linker concentration and less than 20 mg/mL microsphere loadings is more favorable for future application.Translational RelevanceThe investigated DDS is promising for controlled and extended release of anti-VEGF therapeutics to achieve better treatment regimen in ocular neovascularizations.

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. The advantages and disadvantages of each drug delivery system are discussed for various applications. Recommendations for modifications and strategies for improvements to these basic systems are also discussed. Expert opinion: An ideal sustained release drug delivery system should be able to encapsulate and deliver the necessary drug to the target tissues at a therapeutic level without any detriment to the drug. Drug encapsulation should be as high as possible to minimize loss and unless it is specifically desired, the initial burst of drug release should be kept to a minimum. By modifying various biomaterials, it is possible to achieve sustained drug delivery to both the anterior and posterior segments of the eye.

The presence of nanoparticles in beverages has raised great concern in terms of potential impacts to consumer health. Herein, carbon dots in beverages kvass, pony malta, pilsner beer, Vivant Storm, and Profit were identified. They were shown to have a strong fluorescence under the excitation of ultraviolet light. The emission peaks shift to longer wavelengths accompanied by a remarkable fluorescence intensity decrease. The carbon dots are in the nanosized range and roughly spherical in appearance. Elemental analysis by X-ray photoelectron spectroscopy demonstrated the composition of Kvass carbon dots to be C 83.17%, O 13.83%, and N 3.00%. No cytotoxicity was found at concentrations up to 20 mg/mL for human tongue squamous carcinoma cells, and they can be directly applied in both carcinoma and onion epidermal cell imaging. This work represents the first report of the carbon dots present in beverages, providing valuable insights into these nanoparticles for future biological imaging. ABSTRACT:The presence of nanoparticles in beverages has raised great concern in terms of potential impacts to consumer health. Herein, carbon dots in beverages kvass, pony malta, pilsner beer, Vivant Storm, and Profit were identified. They were shown to have a strong fluorescence under the excitation of ultraviolet light. The emission peaks shift to longer wavelengths accompanied by a remarkable fluorescence intensity decrease. The carbon dots are in the nanosized range and roughly spherical in appearance. Elemental analysis by X-ray photoelectron spectroscopy demonstrated the composition of Kvass carbon dots to be C 83.17%, O 13.83%, and N 3.00%. No cytotoxicity was found at concentrations up to 20 mg/mL for human tongue squamous carcinoma cells, and they can be directly applied in both carcinoma and onion epidermal cell imaging. This work represents the first report of the carbon dots present in beverages, providing valuable insights into these nanoparticles for future biological imaging.