Experimental models for investigating drug transport across the round window membrane: implications for inner ear drug delivery and sensorineural hearing loss therapy.

Abstract

The development of effective therapies for inner ear disorders, particularly sensorineural hearing loss (SNHL), requires robust experimental models that accurately evaluate drug delivery systems and therapeutic agents. The round window membrane (RWM) represents the principal anatomical entry site for transtympanic (TT) drug administration to the inner ear and therefore plays a critical role in determining therapeutic efficacy. This review provides a comprehensive overview of the anatomical and physiological characteristics of the RWM and critically examines the experimental approaches used to investigate drug transport across this barrier. In vivo, ex vivo, and in vitro models are compared with respect to their methodological characteristics, translational relevance, advantages, limitations, and most appropriate applications. In vivo models provide integrated information on pharmacokinetics, biodistribution, safety, and therapeutic outcomes, but are limited by biological variability, alternative routes of inner-ear entry, ethical considerations, and cost. Ex vivo systems preserve native tissue architecture in a controlled environment, although tissue availability, viability, and inter-donor variability remain important constraints. In vitro models enable mechanistic studies and higher-throughput screening while reducing animal use but currently lack the full cellular and anatomical complexity of the native human RWM and require further validation. Analytical, imaging, and computational methods used to quantify transport, distribution, and retention are also summarized. Together, these complementary platforms support the rational development of next-generation ototherapeutic strategies.

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