ABSTRACT Sensorineural hearing loss is highly prevalent in military Veterans, but there is currently no biological treatment enabling full restoration of the cochlea and hearing perception. Hearing restoration by stem cell therapy holds great promise. New advances in the generation of inner ear organoids from pluripotent stem cells and our pioneering efforts to condition the cochlea for receiving foreign cells have paved the way forward. However, there remain several major obstacles to combining these approaches. Foremost, there is a lack of a coherent strategy for identifying the right donor cells and tailoring these to the severity of injury in the cochlea. In this proposal, we are focused on stem cell therapy for the severely damaged cochlea, where extreme or chronic injury has reduced the organ of Corti to a flat epithelium of stromal cells that have so far proven refractory to genetic approaches to regeneration. This approach may be the only viable strategy for restoring the full sensory epithelium in older Veterans with long-term hearing loss. Protocols for developing inner ear organoids from pluripotent stem cells produce potential donor cells all along the otic developmental trajectory. Notably, we have developed methods to isolate otic vesicle progenitors from non-otic cells in these cultures, but maturation of the vesicles into sensory epithelia requires a complex, commercial extracellular matrix for efficient differentiation in vitro. In this proposal, we test the hypothesis that multipotent otic progenitors will be required to replace both hair cells and supporting cells in the severely damaged cochlea. The proposal tests the impact of implanting donor cells at various stages of differentiation and examines the role of the extracellular matrix in promoting donor cell survival and maturation. Successful completion of these studies will open new paths toward a viable biological treatment for severe hearing loss.