Developing Inner Ear Organoids in Ultrasound-Activated Piezoelectric Hydrogel for Assessing Ototoxicity

Organoids are capable of recapitulating complex cellular structures and functions, making them valuable tools for drug evaluation, while their use in vitro differentiation of organoids for identifying drug candidates aimed at treating hearing and balance dysfunction remains relatively underexplored. In this study, we present the directed self-organization of human induced pluripotent stem cells within the barium titanate-doped GelMA hydrogel, which promotes the differentiation of inner ear organoids (IEOs) featuring highly differentiated auditory neurons. The hydrogel acting as a sustained source of piezoelectric potential could generate electrical stimulation upon exposure to ultrasonics, thereby facilitating the rapid differentiation and maturation of auditory neurons within IEOs. The bioengineered IEOs form multiple otic-vesicle-like structures and further develop into functional hair cells and sensory neurons. Furthermore, we explored the potential of this model for drug testing, demonstrating that resveratrol effectively mitigates cisplatin-induced toxicity in hair cells and sensory neurons within IEOs. Our electrical stimulation-based approach provides a promising platform for constructing more reliable and functional IEOs, which could serve as an innovative drug screening system for the prevention of cisplatin-induced ototoxicity and neuropathy.