Intracochlear Drug Delivery Through the Oval Window in Fresh Cadaveric Human Temporal Bones

Abstract

Hypothesis Drug delivered to the oval window can diffuse to the apex of the human cochlea. Background We have previously demonstrated that zoledronate, a nitrogen-containing bisphosphonate, can arrest the sensorineural hearing loss in cochlear otosclerosis. We have also shown that, in animals, delivery of bisphosphonate into the cochlea can dramatically increase delivery efficiency. Intracochlear drug delivery has the potential to increase local concentration of drug while decreasing the risk of systemic toxicity. In the present study, a fluorescently labeled bisphosphonate compound (6-FAM-ZOL) was introduced into the human cochlea through the oval window and its distribution within the temporal bone was quantified. Methods In three fresh human temporal bones, we introduced 6-FAM-ZOL via the oval window. We compared these specimens to control specimens treated with artificial perilymph alone. Specimens were then processed, embedded into methyl methacrylate, and ground to the mid-modiolar axis. We quantified the fluorescence in confocal images. Results We found 6-FAM-ZOL to be distributed up to the apical cochlear turn. In specimens treated with 6-FAM-ZOL, we identified a strong baso-apical gradient of fluorescent signal along the lateral cochlear wall and the modiolus both in the scala vestibuli and in the scala tympani. Conclusions Bisphosphonate introduced via the oval window in the human cochlea can be delivered up to the apical cochlear turn. Inter-scalar communication is likely to play an important role in determining patterns of drug delivery in the inner ear.

Translating animal models to human therapeutics in noise-induced and age-related hearing loss

“…Much more needs to be known about the condition of remaining epithelial cells in human ears with different deafness etiologies and durations (deTorres et al, 2018). Other challenges include a lack of knowledge about the relative permeability of the round window membrane to drugs in different species and the dynamics of drug distribution in the larger human cochlea (Kang et al, 2016).…”

Third‐generation bisphosphonates for cochlear otosclerosis stabilizes sensorineural hearing loss in long‐term follow‐up

“…Recently, Kang and colleagues describe non‐ototoxic local delivery of bisphosphonates in guinea pigs using alginate beads at the round window membrane. A second study used fresh human temporal bone specimens for delivery of bisphosphonates using a micropipette at the oval window. Further investigation is still needed to determine the optimal dose and vehicle for local delivery of bisphosphonates into the human inner ear.…”

A radiolabeled drug tracing method to study neurotrophin-3 retention and distribution in the cochlea after nano-based local delivery

“…Furthermore, fluid contamination from cerebrospinal fluid may also compromise the data especially if the sampling volumes are inaccurate. Other approaches such as quantitative MRI/micro CT imaging [3 , 4] , electrophysiological measurements [5] , electrochemical measurements [6] , fluorescently-labeled drug conjugates or tracers [7] , [8] , [9] have also been tested to evaluate cochlear pharmacokinetics, but these techniques provided pharmacokinetic information over only short durations of time (1 h-3 days). Although the fluorescence-based technique allows visualization of drug uptake at cellular level, the use of relatively large fluorophores can alter the drug behavior thus limiting the utility of this approach in understanding drug pharmacokinetics [10] .…”