Round window membrane intracochlear drug delivery enhanced by induced advection

Abstract

Delivery of therapeutic compounds to the inner ear via absorption through the round window membrane (RWM) has advantages over direct intracochlear infusions; specifically, minimizing impact upon functional hearing measures. However, previous reports show that significant basal-to-apical concentration gradients occur, with the potential to impact treatment efficacy. Here we present a new approach to inner ear drug delivery with induced advection aiding distribution of compounds throughout the inner ear in the murine cochlea. Polyimide microtubing was placed near the RWM niche through a bullaostomy into the middle ear cavity allowing directed delivery of compounds to the RWM. We hypothesized that a posterior semicircular canalostomy would induce apical flow from the patent cochlear aqueduct to the canalostomy due to influx of cerebral spinal fluid. To test this hypothesis, young adult CBA/CaJ mice were divided into two groups: bullaostomy approach only (BA) and bullaostomy + canalostomy (B+C). Cochlear function was evaluated by distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) thresholds during and after middle ear infusion of salicylate in artificial perilymph (AP), applied near the RWM. The mice recovered for 1 week, and were re-tested. The results demonstrate there was no significant impact on auditory function utilizing the RWM surgical procedure with or without the canalostomy, and DPOAE thresholds were elevated reversibly during the salicylate infusion. Comparing the threshold shifts for both methods, the B+C approach had more of a physiological effect than the BA approach, including at lower frequencies representing more apical cochlear locations. Unlike mouse cochleostomies, there was no deleterious auditory functional impact after 1 week recovery from surgery. The B+C approach had more drug efficacy at lower frequencies, underscoring potential benefits for more precise control of delivery of inner ear therapeutic compounds.

The Mouse Round-window Approach for Ototoxic Agent Delivery: A Rapid and Reliable Technique for Inducing Cochlear Cell Degeneration

“…This inbred strain is well established as a "good hearing" standard and "normal aging" model in hearing research. [16][17][18][19][20][21][22][23] Description of use of this protocol in other mammalian models is beyond the scope of this text. The reader should note, however, that the RWN application technique offers several advantages to studying the mammalian inner ear.…”

Auditory brainstem gap responses start to decline in mice in middle age: a novel physiological biomarker for age-related hearing loss

“…Using the same procedures as in our previous reports, distortion product otoacoustic emissions (DPOAEs) were used to characterize the functionality of the outer hair cell system (Zhu et al, 2007; Frisina et al, 2011; Borkholder et al, 2013). No medications or other potentially ototoxic procedures were administered.…”

Persistence, distribution, and impact of distinctly segmented microparticles on cochlear health following in vivo infusion

“…It is possible that the differences seen are related to an increase in intracochlear pressure induced by surgery or the viscosity of the delivery solution formed from artificial perilymph and GPSA as this increased trauma was also present when a vehicle solution was used. To alleviate potential pressure changes caused by displacement of native perilymph during infusion, an outlet hole could be drilled to provide an alternative exit to the cochlear aqueduct, thereby enabling removal of excess fluid from the perilymphatic space . Further, future work could include assessment of the functional and pathophysiological impact of the viscosity of the delivery solution and incorporate this knowledge into future iterations of the particle delivery protocol.…”

“…To alleviate potential pressure changes caused by displacement of native perilymph during infusion, an outlet hole could be drilled to provide an alternative exit to the cochlear aqueduct, thereby enabling removal of excess fluid from the perilymphatic space. 26 Further, future work could include assessment of the functional and pathophysiological impact of the viscosity of the delivery solution and incorporate this knowledge into future iterations of the particle delivery protocol. In addition, surface modification could enable particle attachment to implants and eliminate need for a delivery solution.…”