A Non-Invasive Transtympanic Bioadhesive Hydrogel for Sustained Delivery of Dexamethasone in Otitis Media Effusion Therapy.

Otitis media with effusion (OME) is a highly prevalent condition characterized by persistent inflammatory effusion in the middle ear cavity. The clinical management of OME remains challenging due to the anatomical inaccessibility of the middle ear, which limits drug efficacy and often necessitates invasive surgical interventions. To address this, we engineered a transtympanic hydrogel platform (Gel-HADA) that undergoes rapid, enzyme-mediated gelation on the tympanic membrane (TM), forming a "second membrane" through transglutaminase (TGase) crosslinking within 15 min. This hydrogel adheres firmly to the TM, degrades controllably to 5.4 ± 4.0% remaining mass over 7 days, and provides sustained drug delivery. As a result, dexamethasone phosphate disodium-loaded Gel-HADA (Gel-HADA-Dex) demonstrated effective permeability across ex vivo rat TM. In a rat OME model, a single Gel-HADA-Dex administration effectively suppressed mucosal inflammation and restored middle ear function (100% Type A curves, equivalent to the healthy control group). TM thickness (from 91.40 ± 16.46 μm to 8.32 ± 1.60 μm), mucosal thickness (from 67.97 ± 6.21 μm to 46.50 ± 2.47 μm), and leukocyte counts in middle ear lavage (from 140.37 ± 45.94 /HPF to 11.07 ± 1.76 /HPF) were significantly reduced. Mechanistically, Gel-HADA-Dex normalized the aberrant immune-transcriptional network and suppressed key pro-inflammatory cytokines while enhancing anti-inflammatory mediators. The hydrogel demonstrated excellent biocompatibility, hemocompatibility, and auditory safety. Together, the study established Gel-HADA as an innovative, rapid in situ enzymatically crosslinked system for non-invasive transtympanic corticosteroid delivery. Ultimately, it provides a reliable and potentially clinically translatable strategy for localized treatment of OME.