02545nas a2200493   4500000000100000000000100001008004100002260001200043653002200055653001700077653003500094653002300129653002700152100001700179700001500196700001600211700002400227700001700251700001800268700001900286700001200305700001900317700001700336700001500353700001600368700001600384700001600400700001500416700001600431700001600447700002100463700001600484700001800500700002400518700001700542700001600559700001700575245011500592856005500707300001200762490000700774520125600781022001402037       2023                            d  c2023-0110aBiological models10abiomaterials10aExperimental models of disease10aStem-cell research10atranslational research1 aMin Jae Song1 aRuss Quinn1 aEric Nguyen1 aChristopher Hampton1 aRuchi Sharma1 aTea Soon Park1 aCéline Koster1 aTy Voss1 aCarlos Tristan1 aClaire Weber1 aAnju Singh1 aRoba Dejene1 aDevika Bose1 aYu-Chi Chen1 aPaige Derr1 aKristy Derr1 aSam Michael1 aFrancesca Barone1 aGuibin Chen1 aManfred Boehm1 aArvydas Maminishkis1 aIlyas Singec1 aMarc Ferrer1 aKapil Bharti00aBioprinted 3D outer retina barrier uncovers RPE-dependent choroidal phenotype in advanced macular degeneration  uhttps://www.nature.com/articles/s41592-022-01701-1  a149-1610 v203 aAge-related macular degeneration (AMD), a leading cause of blindness, initiates in the outer-blood-retina-barrier (oBRB) formed by the retinal pigment epithelium (RPE), Bruch’s membrane, and choriocapillaris. The mechanisms of AMD initiation and progression remain poorly understood owing to the lack of physiologically relevant human oBRB models. To this end, we engineered a native-like three-dimensional (3D) oBRB tissue (3D-oBRB) by bioprinting endothelial cells, pericytes, and fibroblasts on the basal side of a biodegradable scaffold and establishing an RPE monolayer on top. In this 3D-oBRB model, a fully-polarized RPE monolayer provides barrier resistance, induces choriocapillaris fenestration, and supports the formation of Bruch’s-membrane-like structure by inducing changes in gene expression in cells of the choroid. Complement activation in the 3D-oBRB triggers dry AMD phenotypes (including subRPE lipid-rich deposits called drusen and choriocapillaris degeneration), and HIF-α stabilization or STAT3 overactivation induce choriocapillaris neovascularization and type-I wet AMD phenotype. The 3D-oBRB provides a physiologically relevant model to studying RPE–choriocapillaris interactions under healthy and diseased conditions.  a1548-7105