Inner Ear Organoids: Recent Progress and Challenges.

Abstract

Hearing loss is a prevalent sensory disorder primarily caused by the irreversible loss of cochlear hair cells and the limited regenerative capacity of the mammalian inner ear. The structural complexity and inaccessibility of inner ear tissues have long hindered mechanistic studies and therapeutic development. In recent years, inner ear organoids have emerged as a robust in vitro platform that recapitulates key aspects of inner ear development, cellular composition, and functional organization. Derived from pluripotent stem cells or tissue-specific progenitors, inner ear organoids exhibit intrinsic self-organizing capabilities under the spatiotemporal regulation of developmental signaling pathways, including TGF-β, BMP, FGF, and Wnt. These systems enable the generation of hair cell-like cells, supporting cells, and neuronal components, thereby providing a powerful tool for investigating developmental processes and disease mechanisms. Notably, patient-specific induced pluripotent stem cell-derived organoids facilitate modeling of hereditary hearing disorders and enable personalized therapeutic screening. Beyond basic research, inner ear organoids hold significant promise for drug discovery, ototoxicity assessment, and gene therapy validation. However, current models still face several limitations, including incomplete cellular heterogeneity, insufficient functional maturation, lack of vascularization and immune components, and variability across culture systems. Emerging bioengineering approaches, such as organ-on-a-chip platforms, synthetic biomaterials, and 3D bioprinting, are expected to enhance the physiological relevance and translational potential of these models. In this review, we summarize recent advances in the generation of inner ear organoids, discuss their applications in basic and translational research, and highlight current challenges and future directions toward clinical translation.