Age-related macular degeneration (AMD), a leading cause of blindness, initiates in the outer-blood-retinabarrier (oBRB) formed by Retinal pigment epithelium (RPE), Bruch's membrane, and choriocapillaris. The mechanism of AMD initiation and progression remain poorly understood due to the lack of physiologically relevant oBRB models. We engineered a native-like 3D-oBRB tissue 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, a fully-polarized RPE monolayer with apical processes and basal infoldings provides barrier resistance, induces fenestration and choroid-specific gene expression in the choriocapillaris, and supports the formation of a Bruch's-like membrane that allows tissue integration in rat eyes. Complement activation in the 3D-oBRB triggers dry-AMD phenotypes (including subRPE drusen and choriocapillaris degeneration), and hypoxia activated HIF-α induces wet-AMD phenotypes (choriocapillaris neovascularization). Anti-VEGF drug treatment suppresses neovascularizationvalidating this model for clinical translation and drug discovery.

IMPORTANCEAfter the Age-Related Eye Disease Study 2 (AREDS2) study, the beta carotene component was replaced by lutein/zeaxanthin for the development of the revised AREDS supplement. However, it is unknown if the increased risk of lung cancer observed in those assigned beta carotene persists beyond the conclusion of the AREDS2 trial and if there is a benefit of adding lutein/zeaxanthin to the original AREDS supplement that can be observed with long-term follow-up.OBJECTIVE To assess 10-year risk of developing lung cancer and late age-related macular degeneration (AMD).

Development of new non-addictive analgesics requires advanced strategies to differentiate human pluripotent stem cells (hPSCs) into relevant cell types amenable for translational research. Here, we developed a highly efficient and reproducible method that differentiates hPSCs into peptidergic and non-peptidergic nociceptors. By modulating specific cell signaling pathways, hPSCs were first converted into SOX10+ neural crest cells, followed by differentiation into sensory neurons with an in vivo-like pseudo-unipolar morphology. Detailed characterization confirmed that the hPSC-derived nociceptors displayed molecular and cellular features comparable to native dorsal root ganglion (DRG) neurons, and expressed high-threshold primary sensory neuron markers, transcription factors, neuropeptides, and over 150 ion channels and receptors, including critical pain-relevant drug targets (e.g., TRPV1, TAC1, CALCA, NAV1.7, NAV1.8). Moreover, after confirming robust functional activities and differential response to noxious stimuli and specific drugs, a robotic cell culture system was employed to produce large quantities of human sensory neurons, which can be used to develop nociceptor-selective analgesics.