(A-14) Optimizing Biomaterial Formulations for the Topical Treatment of Age-Related Macular Degeneration

Introduction:: The World Health Organization estimates that in 2020 there were around 196 million people with age-related macular degeneration (AMD), which has become the leading cause of blindness in patients over 65 years of age. This disease is characterized by the development of vascularization at the choroid, the vascular layer of the retina, which leads to severely damaged photoreceptors. Its current and only form of treatment is through monthly intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF). However, in addition to being highly inconvenient and uncomfortable, intravitreal injections also pose a significant financial burden to patients from marginalized communities since the injections are extremely expensive, thus creating an important source of inequity in eyecare access. As a result, the ocular field is increasingly invested in developing topical treatments for AMD as a less invasive and more accessible alternative. However, a key challenge to topical formulations is that the bioavailability of drugs administered to the eye via topical formulations is very low, with only 5-10% of the active therapeutic entering the eye. To address this challenge, our goal is to develop a topical drug delivery platform for the treatment of posterior eye segment diseases like AMD. Specifically, in this study we have optimized mucoadhesive and environmentally responsive polymeric biomaterial formulations with anionic nanoparticles for their use in topical ocular drug delivery to the posterior eye segment.


Materials and Methods:: In situ gel formulations were fabricated using Pluronic F-127, a triblock co-polymer of Poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), as a temperature sensitive material. The ability of this material to undergo a phase transition at body temperature (37 °C) was modulated to a transition temperature equal or below the surface temperature of the eye (35 °C). Chitosan, alginate, and poly(acrylic acid) were selected as mucoadhesive agents and were mixed with the Pluronic F-127 material at 2 different concentrations to obtain mucoadhesive and temperature sensitive formulations. The formulations were evaluated for optical transparency using ultraviolet-visible spectroscopy. To determine the impact of Pluronic F1-27 concentration on the gelling temperature of the formulations, four different concentrations were tested and the impact of adding a mucoadhesive agent on the dynamic viscoelastic behavior of the formulations was studied using rheometry.

Self-assembled anionic nanoparticles of fluorinated hyaluronic acid (HA) were synthesized via carbodiimide coupling of HA and perfluoroheptanoic acid (PFHA). Feed ratios of PFHA were varied and their impact on nanoparticle size and charge was studied using dynamic light scattering (DLS).


Results, Conclusions, and Discussions:: As expected, gelling temperature of the biomaterial formulations decreased as the concentration of Pluronic F-127 increased. All the formulations had excellent optical properties with light transmittance values above 80%. The presence of the 3 mucoadhesive agents showed minimal impact on the gelling temperature of the formulations or their optical properties. For the nanoparticles, feed ratio of PFHA was identified as a strategy for modulating the size of FHA nanoparticles (Figure 1).

Developing smart biomaterial formulations with excellent optical properties, tunable thermoresponisve behavior, and integrated nanotechnology is a critical milestone in the development of topical formulations for the treatment of posterior eye segment diseases. Future development of this topical drug delivery platform could provide millions of patients with more accessible treatments and major impact on blindness prevention.


Acknowledgements (Optional): : This work was supported by the NIH (R01-EB022025), the Cockrell Family Chair Foundation, the Office of the Dean of the Cockrell School of Engineering at the University of Texas at Austin (UT) for the Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, and the UT-Portugal Collaborative Research Program. JJR-C was supported by the National Science Foundation Graduate Research Fellowship under Grant No. 2137420.

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