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Development of vascularized human retinal organoids to model age related macular degeneration (AMD)

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Recently, methods to produce 3D retinal organoids, potentially tremendously useful tools for developmental and regenerative research, from iPSCs and ESCs have been developed. However, current approaches are limited in their ability to create retinal organoids that recapitulate the complexity and functionality of the retina. In particular, current retinal organoids cultures lack proper spatial organization of a retinal pigmented epithelium (RPE) relative to neural retina and organization of retinal layers. In addition, current retinal organoid systems lack vasculature, and thereby are limited in availability of nutrients and oxygen supply to the culture system, constraining the size of the organoids that can be grown and the disease states that can be meaningfully explored. To address the shortage of spatial control within developing retinal organoids, we propose to create a biomimetic gradient of chemical and physical cues recapitulating those present during retinal development, rather than an isotropic environment lacking spatial variation in cues. To overcome the lack of vascularization and aid in establishment of these gradients, a bioengineering approach using microfluidic chambers will be employed to enable in situ development of vasculature driving the flow of fluid through a biomimetic hydrogel-based “choroid” on which retinal organoids will be grown. The hydrogel properties, including chemical composition and stiffness (elastic modulus of the retina is 0.431 MPa), will be systematically varied to promote the selective attachment and proliferation of the retinal pigment epithelium cells within growing organoids, and the spatiotemporal control afforded by the microfluidic platform will be used to impart a gradient of signaling cues across the growing organoids to allow proper orientation of layers recapitulating a physiologically relevant laminated retina. The engineering of a system enabling examination of interaction of blood vessels and retinal tissue during organoid development and culture offers high potential for understanding development of the eye and modeling retinal diseases including age related macular degeneration (AMD)

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