A viscosity-tunable microgel-in-sol phase for localized inner ear delivery of small hydrophilic drug

Cisplatin-induced ototoxicity leads to irreversible hearing loss in approximately 50% of treated patients, largely due to the cochlea's exceptionally poor cisplatin clearance compared with other organs. Although sodium thiosulfate (STS), a hydrophilic small molecule, is an established otoprotectant, achieving therapeutically sufficient cochlear concentrations remains challenging because systemic administration is limited by the blood-labyrinth barrier. Here, we report a viscosity-tunable microgel-in-sol system based on hyaluronic acid (HA) that enables sustained, localized delivery of STS to the inner ear via intratympanic injection. The STS-loaded microgel was readily injectable through 31 G needles and provided a six-fold extension in drug release duration compared with free STS solution. However, direct microgel injection caused significant occlusion of the middle ear cavity due to swelling and poor clearance. To overcome this limitation, we developed a microgel-in-sol formulation composed of an HA solution and microgel at a 3:1 volumetric ratio. This formulation exhibited concentration-dependent, lubricant-like viscosity while maintaining effective drug delivery and preserving auditory function, as confirmed by in vivo auditory brainstem response (ABR) measurements. Overall, this microgel-in-sol strategy represents a biocompatible, minimally invasive approach for localized inner-ear drug delivery.