The round window membrane in the sheep cochlea

Abstract

Hearing loss is the most prevalent form of sensory impairment. Development of novel therapeutic approaches for hearing loss is hindered by lack of effective methods for local drug delivery to the inner ear. This is challenged by the anatomical structure and location of the inner ear organ, the cochlea, encapsulated deep in the temporal bone of the skull. Intratympanic drug administration is a commonly used clinical method for drug delivery to the inner ear and involves direct injection of the drug to the middle ear cavity followed by drug diffusion through the round window membrane (RWM) into the cochlea. The selective permeability of the RWM is thought to pose limitations on the molecular size and the amount of drugs that can be delivered using this approach. Surprisingly, there is relatively little information on the structure and cellular composition of the RWM. The sheep is considered as an appropriate large animal model for human inner ear therapeutics due to the anatomical similarities between human and sheep auditory systems. As such the aim of this study was to characterize the three-dimensional structure and cellular composition of the sheep RWM using three complementary imaging techniques; μCT, histology and confocal microscopy. Qualitative and quantitative analysis of the sheep RWM revealed a complex 3D structure and identified distinct zones by differences in curvature, thickness within the RWM and attachment to surrounding bone. A three-layered structure comprised of an outer epithelial layer, middle connective tissue and inner epithelial layer was identified and revealed cellular features such as actin filaments, melanocytes and a “meshwork structure”. The imaging techniques used successfully identified and confirmed similarities in size and structures between sheep RWM and those reported for human RWM and provided an anatomically orientated guide map of the sheep RWM which can be applied for more accurate comparisons with human RWM in future studies. Lastly, the structural and cellular similarities between sheep and human RWM suggests sheep to be an excellent large animal model to evaluate drug uptake and to the development of novel methods for safe and effective drug delivery to the inner ear.