An injectable bioadhesive hyaluronic acid hydrogel formulated with drug-loaded microparticle cross-linkers for co-delivery of dexamethasone and lidocaine to the inner ear

Combination therapies with two or more drugs administrated by intratympanic (IT) injection represent a promising strategy for the treatment of sensorineural hearing loss (SNHL), an inner ear disease imposing a substantial burden on patients. However, the therapeutic outcomes of conventional liquid formulations have been hindered by poor drug retention in the middle ear cavity. In the present study, a versatile hydrogel (CT Gel) was engineered for co-delivery of dexamethasone and lidocaine with drug-loaded microparticles as both cross-linkers and modular drug reservoirs. Specifically, dexamethasone microcrystals and lidocaine-loaded poly (lactic-co-glycolic acid) (PLGA) microspheres were separately prepared and subsequently coated with polydopamine (PDA). The resulting PDA-functionalized microparticles were then employed to crosslink phenylboronic acid-modified hyaluronic acid via dynamic covalent boronate ester bonds, thereby forming the hydrogel. CT Gel exhibited injectable, bioadhesive, antioxidant and sustained-release properties. Moreover, it was shown that, following IT administration in guinea pigs, CT Gel persisted in the middle ear cavity for over 7 days, enhanced drug exposure in the perilymph, and exhibited favorable biocompatibility. We anticipate that such hydrogels, crosslinked using drug-loaded microparticles as modular drug reservoirs, will find broad applications in the combinatorial treatment of inner ear disorders.