Local Drug Delivery to the Entire Cochlea without Breaching Its Boundaries

Abstract

The mammalian cochlea is one of the least accessible organs for drug delivery. Systemic administration of many drugs is severely limited by the blood-labyrinth barrier. Local intratympanic administration into the middle ear would be a preferable option in this case, and the only option for many newly emerging classes of drugs, but it leads to the formation of drug concentration gradients along the extensive, narrow cochlea. The gradients are orders of magnitude and well outside the therapeutic windows. Here we present an efficient, quick, and simple method of cochlear pumping, through large-amplitude, low-frequency reciprocal oscillations of the stapes and round window, which can consistently and uniformly deliver drugs along the entire length of the intact cochlea within minutes without disrupting the cochlear boundaries. The method should facilitate novel ways of approaching the treatment of inner ear disorders because it overcomes the challenge of delivering therapeutics along the entire cochlear length.

Keywords: Audiology; Biotechnology; Drug Delivery System.

Graphical abstract

Figure 1

Effect of the CP on the Neural Responses in the Absence and Presence of Salicylate on the RW (A) Representative examples of CAP threshold curves in the presence of CP alone. Pressure oscillations at 4 Hz that caused ∼80 μm peak-to-peak stapes displacement were applied to the ear canal during 5 min before each non-zero time point plotted, and the CAP thresholds were measure during the following 5-min interval without CP. The legend indicates the cumulative pumping time for each curve. Solid black line and vertical bars indicate the mean ± SD for all seven curves, each representing a different cumulative pumping time. (B) A representative example of CAP threshold elevation when the same pumping protocol as in (A) was used after the application of 5 μL of 100 mM salicylate solution to the RW at time zero and recovery of the thresholds after washing out the salicylate. The frequency of the pure tone acoustic stimulation used for eliciting the CAP is indicated in the figure legend for each curve.

Figure 2

Comparison of the Efficiency of the CP Technique and Passive Diffusion in the Distribution of Salicylate along the Cochlea Pooled data for experiments with CP (red symbols, five preparations) and passive diffusion (black symbols, five preparations; Sadreev et al., 2019). Pressure oscillations at 4 Hz were applied to the ear canal during 5 min before each red non-zero time point plotted to cause large-amplitude (∼80 μm peak-to-peak) stapes movement, and the CAP thresholds were measured during the following 5-min interval without pressure oscillation. Frequency of acoustic stimulation is indicated within each panel; 5 μL of 100 mM salicylate solution was applied to the RW at time zero. Solid red lines indicate mean CP data, and solid black lines indicate 5-point running averages for passive diffusion data. Gray lines near the horizontal axis indicate statistically significant (p < 0.05, unpaired t test) differences between data for the CP and passive diffusion within consecutive 10-min intervals. Some of the passive diffusion data have been presented before (Sadreev et al., 2019).

Figure 3

Comparison of Frequency Dependence of the CP and Passive Diffusion Effects Frequency dependence of the CAP threshold elevation after 60 min of salicylate application during CP (35 min of the total pumping time) (mean ± SD, n = 5) and its comparison with the frequency dependence for passive diffusion (mean ± SD, n = 5). Open circles show maximal increase of the CAP thresholds after complete block of the cochlear amplifier (mean ± SD, n = 3) (Sadreev et al., 2019). Data for passive diffusion have been partially presented before (Sadreev et al., 2019).