In situ forming hydrogel for sustained intraocular drug delivery

Purpose Delivery of therapeutic proteins to the posterior segment of the eye faces significant challenges because of frequent intraocular injections, related adverse effects and high treatment costs. This research project aims to design in situ forming hydrogels, which can be easily injected in the vitreous cavity using a small needle. After injection, the polymeric solution undergoes a phase transition to form a cross‐linked hydrogel at the site of administration, entrapping bioactives, which will be released over a prolonged period. In this study, Hyaluronic acid‐modified with furan moieties (HAFU) was successfully crosslinked with four arm‐PEG10K‐maleimide (4APM) yielding stable hydrogels. The potential use of this system for ocular applications was shown by testing the injectability, sustained release of a therapeutic protein and cytocompatibility to retinal cells. Methods & Results HAFU‐4APM hydrogels were prepared by mixing an aqueous solution of HAFU and 4APM at physiological conditions to obtain transparent hydrogels. Rheological analysis showed rapid hydrogel network formation at 37°C. The gelation time and final hydrogel stiffness are strongly dependent on polymer concentration. Hydrogel solutions could be injected to the vitreous body of a porcine eye through a 29G needle. Swelling and degradation analysis showed that the hydrogel system is degradable at physiological conditions. The hydrogels showed no toxicity to retinal cells at the used concentrations. HAFU‐4APM hydrogels could sustain the delivery of bevacizumab for 71 days. Conclusion Injectable in situ forming hydrogels have been prepared for the sustained retinal delivery of bevacizumab. The formulation has potential for the treatment of age‐related macular degeneration and diabetic retinopathy. Acknowledgements This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska‐Curie grant agreement No 722717.