Exploiting cochlear hydrodynamics for uniform and non-invasive drug delivery along the entire intact cochlea

Effective treatment of peripheral hearing disorders such as sudden-onset hearing loss, with potential to cause devastating sensory and social impairment, requires fast, easy, and non-invasive delivery of therapy throughout the cochlea. Currently, this requirement is clinically unavailable. Buried in a hard bone in the skull and twisted into a tight spiral, the human cochlea is one of the least accessible organs for drug delivery. Systemic administration of many drugs, including frequently used corticosteroids, is severely limited by the blood-labyrinth barrier. Local intratympanic administration into the middle ear would be the method of choice and the only option for many established and newly emerging classes of drugs. This approach relies on drugs remaining in contact with the membranous round window in the bony wall of the cochlea for long enough to allow their diffusion into the cochlear fluid. The ability of drugs to pass through the round window does not, however, lead to their effective distribution along the long and narrow cochlear spiral. The concentration of drugs resulting from diffusion through the round window is high at the base of the cochlear spiral, but far lower in the distant apex, where human speech processing is initiated, and where drug delivery to the cochlea has the greatest potential for therapeutic and socioeconomic impact. We have discovered a transformative method that can consistently and uniformly deliver drugs along the whole cochlea within minutes. The method combines intratympanic drug administration and cochlear pumping, through large amplitude, low-frequency pressure changes delivered to the external ear. In published animal studies, we have demonstrated that the technique does not excite the sound-sensitive hair cells and promotes uniform drug distribution along the entire length of the intact cochlea. We now aim to establish safe and optimal regimes for uniform cochlear drug delivery that could be applicable to human patients. We will obtain optimal parameters for cochlear pumping for a range of drugs with different physicochemical properties. Because direct experiments in human patients are not feasible, the project objective will be achieved through combining physiological and histochemical experiments and cochlear fluid drug concentration measurements in animal studies with mathematical modelling of cochlear fluid mechanics and diffusion processes in animal and human cochleae. This research will provide insight into the fundamental hydrodynamics of the cochlea, which is critical for understanding the workings of a hydrodynamic device like the inner ear. Also, the project will deliver protocols to achieve uniform, non-invasive drug delivery in human patients to initiate clinical studies of the method efficacy. In the short term, a wide range of patients suffering from hearing disorders, with indication for intratympanic drug administration will benefit from results of the proposed project. For example, the project will lead to an immediate increase in the efficacy and consistency of intratympanic applications of corticosteroids used as a first line of treatment for sensorineural hearing loss (including noise-induced hearing loss), tinnitus, Ménière’s disease and autoimmune inner ear disease. In the longer term, through offering a generic approach for delivering therapeutic compounds to the entire cochlea, our method will provide a platform for future drug development studies and reassurance that the therapeutic targets can be reached.