Woo Seok Kang1, Kim Nguyen, Charles E McKenna, William F Sewell, Michael J McKenna, David H Jung. 1. *Department of Otolaryngology, Massachusetts Eye and Ear Infirmary†Eaton Peabody Laboratory, Massachusetts Eye and Ear Infirmary‡Department of Otology and Laryngology, Harvard Medical School, Boston, Massachusetts§Department of Chemistry, University of Southern California, Los Angeles, California.
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. CONCLUSION: Bisphosphonate introduced via the oval window in the human cochlea can be delivered up to the apical cochlear turn. Interscalar communication is likely to play an important role in determining patterns of drug delivery in the inner ear.
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. CONCLUSION:Bisphosphonate introduced via the oval window in the human cochlea can be delivered up to the apical cochlear turn. Interscalar communication is likely to play an important role in determining patterns of drug delivery in the inner ear.
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