A Next Generation Outer Retinal Microphysiological System

ABSTRACT The discovery of induced pluripotent stem cells (iPSCs) provided scientists with the opportunity to develop differentiated tissues from patients with inherited disease, and to use these in vitro models to study disease mechanisms and to test drug and gene-based therapeutics. However, current differentiation protocols often fail to accurately recapitulate the cellular organization present in the native tissue. For example, even state-of-the- art retinal differentiation protocols, which give rise to three dimensional retinal organoids, do not accurately recapitulate the cell-cell interactions that are present in the outer retina. Specifically, choroidal endothelial cells are rarely present and never form an organized layer beneath the RPE. Similarly, rather than forming a monolayer juxtaposed to newly developed photoreceptors, RPE cells are often found in clusters located at the edges of the neural retina. In this application we describe a program focused on the development and validation of a microphysiological system engineered to accurately recreate the complex architecture of the perfused outer retina. Specifically, we propose to combine ultra-high resolution, state-of-the-art 3D printing of retinal scaffolds, iPSC technology, and microfluidics to develop a next generation microphysiological system that recapitulates the outer retina unit. Completion of the aims outlined in this proposal will help pave the way for future studies focused on evaluating the pathophysiology of complex retinal degenerative disorders such as age-related macular degeneration and development of novel drug and gene-based therapeutics.