Photocrosslinked Mucoadhesive Hyaluronic Acid Hydrogel for Transmucosal Drug Delivery

Drug delivery to the central nervous system (CNS) is primarily hindered by the blood-brain barrier (BBB). To address this, mucoadhesive formulations have been designed to prolong residence time at the application site. In this study, we comprehensively characterized the physicochemical and mucoadhesive properties of hyaluronic acid tyramine (HATA) photocrosslinked hydrogels using rheological methods, nanoindentation, contact angle goniometry, and advanced confocal microscopy. A novel parameter, photon count per pixel, was introduced through confocal microscopy to assess hydrogel stability and mucoadhesion on ex vivo porcine olfactory tissues. Crosslinked hydrogels (1% and 2% w/v) exhibited stable mucoadhesive properties, ranging between 16.5 and 18 photon counts per pixel, whereas uncrosslinked counterparts typical of classical nasal formulations showed significant photon count losses (71% and 50% for 1% and 2% HATA, respectively). Nanoindentation analysis revealed a correlation between photoirradiation time, effective Young's modulus, and mucoadhesion, identifying 1 min of irradiation as optimal across all concentrations tested. The optimized hydrogels demonstrated mucoadhesive forces of 0.263, 0.412, and 0.701 mN mm^-2, corresponding to Young's modulus values of 1995, 2465, and 2985 Pa for 1%, 2%, and 3% w/v HATA, respectively. These results highlight the importance of crosslinking for enhancing hydrogel stability and mucoadhesion. Additionally, BSA-labeled rhodamine served as a model protein drug in low-swelling hydrogels for drug release studies, laying the foundation for further optimization in targeted nasal drug delivery systems.