Local Drug Delivery to the Entire Cochlea without Breaching Its Boundaries

Abstract

Systemic delivery of drugs to the inner ear is limited by the blood-labyrinth barrier Middle ear administration results in pronounced drug gradients along the cochlea Cochlear pumping distributes drugs evenly along the entire cochlea within minutes

Drug distribution along the cochlea is strongly enhanced by low-frequency round window micro vibrations

“…This frequency dependence of drug distribution also indicates that placement of the RW probe did not rupture the RW. At the same time, the enhanced effect on the CAP threshold elevation in the basal half of the cochlea, produced by the RW vibrations ( Figure 5 ), compared to passive diffusion (Sadreev et al, 2019 ) and cochlear pumping (Lukashkin et al, 2020 ), suggests that the RW drug permeability for salicylate was increased during direct mechanical stimulation of the RW.…”

“…This effectively means that salicylate is not able to reach the apical 50% of the cochlea at any effective concentrations. Combined application of salicylate and low-frequency (4 Hz) pressure oscillations to the ear canal (cochlear pumping), which causes large amplitude (80 µm peak-to-peak), movement of the stapes and reciprocal movement of the RW, causes elevation of CAP thresholds within the entire frequency range tested ( Figure 5 , blue line; Lukashkin et al, 2020 ). This indicates the ability of the cochlear pumping to distribute salicylate evenly along the entire cochlea.…”

“… Comparison between different techniques of drug delivery through the RW. Frequency dependence of the CAP threshold elevation after 60 min of 5 µl, 100 mM salicylate solution application for three models of drug distribution: for passive diffusion (black line, mean ± SD, N = 5, Lukashkin et al, 2020 ), during cochlear pumping through application of low-frequency pressure oscillations to the ear canal (35 min of the total pumping time) (blue line, mean ± SD, N = 5, from Lukashkin et al, 2020 ) and continuous RW probe vibrations at 4 Hz (red line, mean ± SD, N = 6) are shown. Open circles show maximal increase of the CAP thresholds after complete block of the cochlear amplifier by application of 5 µl of 1 M salicylate solution to the RW (mean ± SD, N = 3) (Sadreev et al, 2019 ).…”

“…For a given geometry of the scala tympani, the steady-state drug concentration gradient (denoted by the blue color intensity) along it depends only on the ratio kd/kc (Sadreev et al, 2019 ). (A) is modified from (Lukashkin et al, 2020 ).…”

“…A few relatively noninvasive techniques for assisting substance mixing along the cochlea have been suggested recently that utilize low-frequency pressure stimulation (Lukashkin et al, 2020 ), stimulation at acoustic frequencies (Park & Moon, 2014 ; Shokrian et al, 2020 ) and ultrasound (Liao et al, 2020 ) which cause reciprocated movement of the stapes and RW. While the later method relies on the formation of ultrasound-induced microbubbles which can act directly on the RW (Liao et al, 2020 ), the other techniques require the mobility of the ossicular chain.…”