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Transparency is an important criterion for the application of biomaterials to the eye and essential for use as a vitreous substitute. However, there is a lack of understanding on the features of transparent hydrogels and the boundaries of transparency of various hydrogel systems. In this paper, we tune the poly[(R)-3-hydroxybutyrate-(R)-3-hydroxyhexanoate] (PHBHx) content of biodegradable PHBHx-based polyurethane thermogels and show that the amount of hydrophobic PHBHx correlates with hydrogel cloudiness. We found that PHxEP-0.5 hydrogel shows high light transmittance and suitable gel properties as a vitreous substitute. The PHxEP-0.5 hydrogel is able to maintain transparency when implanted in rabbit eyes as opposed to a cloudy gel and shows negligible inflammation and preservation of the retinal structure over 6 months. In conclusion, we show that PHBHx-based thermogels can be tuned for transparency and are biocompatible in the rabbit eye. These results could be instructive for the design of a new generation of injectable transparent vitreous substitutes.

Anti-vascular endothelial growth factor (anti-VEGF) proteins are the gold-standard treatment for posterior eye segment proliferative vascular diseases such as Age-Related Macular Degeneration (AMD) and Diabetic Retinopathy (DR). However, the standard of care requires inconvenient monthly intravitreal injections. This underlies an unmet clinical need to develop alternative solutions for sustained delivery of biologics. In this paper, we demonstrated that anti-VEGFs can be encapsulated by a simple mild process into our polyurethane thermogel depots. By changing the hydrophilic–hydrophobic balance in the copolymer, anti-VEGF release rates can be modulated. The antibody in the thermogel partitions into protein domains which vary in size corresponding to the hydrophilicity balance of the polymer. Anti-VEGFs can be released in a relatively linear manner from the thermogel for up to 40 days in vitro. The encapsulated anti-VEGFs demonstrate anti-angiogenic bioactivity by inhibiting vessel outgrowth in rat ex vivochoroidal explants, and reducing vascular leakage in a VEGF-driven neovascularization rabbit model. In conclusion, we show that these thermogels can be tuned in terms of hydrophilicity and used for sustained delivery of bioactive anti-VEGFs. Physically cross-linked polyurethane thermoresponsive hydrogels could be a promising platform for sustained delivery of biologically active therapeutic proteins.