Ultrasound-induced microbubble (USMB) cavitation is widely used to promote drug delivery. Our previous study investigated USMB targeting round window membrane by applying the ultrasound transducer to tympanic bulla. In the present study we further extended the use of this technology to enhance drug delivery to inner ear by introducing the ultrasound transducer into external auditory canal (EAC) or applying it to skull. Using a three-dimensional-printed diffusion apparatus mimicking the pathway for ultrasound passing through and reaching middle ear cavity in vitro, both models simulating the transcanal and transcranial approach demonstrated 4.8-fold and 3.7-fold higher delivery efficiencies, respectively. In vivo model of guinea pigs, by filling tympanic bulla with microbubbles and biotin-fluorescein (biotin-FITC), USMB applied transcanally and transcranially induced 2.8-fold and 1.5-fold increases in biotin-FITC delivery efficiencies, respectively. In addition, the gentamicin uptake by cochlear and vestibular hair cells and gentamicin-induced hair cell loss were significantly enhanced following transcanal application of USMB. On the 28th day after transcanal USMB, safety assessment showed no significant changes in the hearing thresholds and the integrity of cochlea. These are the first results to demonstrate the feasibility and support the potential clinical application of applying USMB via EAC to facilitate drug delivery into inner ear.
Ai-Ho Liao, Chih-Hung Wang, Ping-Yu Weng, Yi-Chun Lin, Hao Wang, Hang-Kang Chen, Hao-Li Liu, Ho-Chiao Chuang, Cheng-Ping Shih