Semicircular canal drug delivery safely targets the inner ear perilymphatic space
Jinkyung Kim, Jesus Maldonado, Dorothy W. Pan, Patricia M. Quiñones, Samantha Zenteno, John S. Oghalai, Anthony J. Ricci
Jinkyung Kim, Jesus Maldonado, Dorothy W. Pan, Patricia M. Quiñones, Samantha Zenteno, John S. Oghalai, Anthony J. Ricci
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Research Article Otology Therapeutics

Semicircular canal drug delivery safely targets the inner ear perilymphatic space

Abstract

Effective, reproducible, and safe delivery of therapeutics into the inner ear is required for the prevention and treatment of hearing loss. A commonly used delivery method is via the posterior semicircular canal (PSCC); however, its specific targeting within the cochlea remains unclear, impacting precision and reproducibility. To assess safety and target specificity, we conducted in vivo recordings of the pharmacological manipulations delivered through the PSCC. Measurements of auditory brainstem response (ABR), vibrometry, and vestibular behavioral and sensory-evoked potential (VsEP) revealed preserved hearing and vestibular functions after artificial perilymph injections. Injection of curare, a mechanoelectrical transducer (MET) channel blocker that affects hearing when in the endolymph, had no effect on ABR or VsEP thresholds. Conversely, injection of CNQX, an AMPA receptor blocker, or lidocaine, a Na+ channel blocker, which affects hearing when in the perilymph, significantly increased both thresholds, indicating that PSCC injections selectively target the perilymphatic space. In vivo tracking of gold nanoparticles confirmed their exclusive distribution in the perilymph during PSCC injection, supporting the pharmacological finding. Together, PSCC injection is a safe method for inner ear delivery, specifically targeting the perilymphatic space. Our findings will allow for precise delivery of therapeutics within the inner ear for therapeutic and research purposes.

Authors

Jinkyung Kim, Jesus Maldonado, Dorothy W. Pan, Patricia M. Quiñones, Samantha Zenteno, John S. Oghalai, Anthony J. Ricci

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Figure 2

Auditory brainstem response (ABR) after artificial perilymph injection through the PSCC.

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Auditory brainstem response (ABR) after artificial perilymph injection t...
(A) Representative ABR responses at 16 kHz before, 5 minutes after, and 1 hour after artificial perilymph (AP) injection. Purple lines indicate thresholds of the ABR responses. (B) ABR thresholds before, 5 minutes after, and 1 hour after AP injection (n = 5). While the thresholds increased 5 minutes after the injection as compared with preinjection (*P < 0.05, **P < 0.01 by paired, 2-tailed Student’s t test), no statistically significant shifts were observed between preinjection and 1 hour after the injection (P > 0.05 by paired, 2-tailed Student’s t test). (C) ABR thresholds before and 5 minutes after tube insertion (i.e., no injection) (n = 5). *P < 0.05, **P < 0.01 by paired, 2-tailed Student’s t test. (D) Threshold changes before and 5 minutes after injection (panel B: light purple line) and tube insertion (panel C: light blue line). P > 0.05 by unpaired, 2-tailed Student’s t test. (E) Individual animal responses to click ABRs measured before and every 15 minutes after injection. Boxes, SD; stars, mean; lines, median (n = 15). *P < 0.002, 0.003, 0.001, 0.004, and 0.03 for the 15, 30, 45, 60, and 75 minute time points, respectively, by paired, 2-tailed Student’s t test. (F) Plots the number of animals showing greater than 10 dB (red) or less than 10 dB (black) threshold shifts after injection against time after injection. By 60 minutes, no animals had greater than 10-dB shifts.