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Over the last decade, scientists have begun to model CNS development, function, and disease in vitro using human pluripotent stem cell (hPSC)-derived organoids. Using traditional protocols, these 3D tissues are generated by combining the innate emergent properties of differentiating hPSC aggregates with a bioreactor environment that induces interstitial transport of oxygen and nutrients and an optional supportive hydrogel extracellular matrix (ECM). During extended culture, the hPSC-derived neural organoids (hNOs) obtain millimeterscale sizes with internal microscale cytoarchitectures, cellular phenotypes, and neuronal circuit behaviors mi-metic of those observed in the developing brain, eye, or spinal cord. Early studies evaluated the cytoarchitectural and phenotypical character of these organoids and provided unprecedented insight into the morphogenetic processes that govern CNS development. Comparisons to human fetal tissues revealed their significant simila-rities and differences. While hNOs have current disease modeling applications and significant future promise, their value as anatomical and physiological models is limited because they fail to form reproducibly and re-capitulate more mature in vivo features. These include biomimetic macroscale tissue morphology, positioning of morphogen signaling centers to orchestrate appropriate spatial organization and intra- and inter-connectivity of discrete tissue regions, maturation of physiologically relevant neural circuits, and formation of vascular net-works that can support sustained in vitro tissue growth. To address these inadequacies scientists have begun to integrate organoid culture with bioengineering techniques and methodologies including genome editing, bio-materials, and microfabricated and microfluidic platforms that enable spatiotemporal control of cellular differentiation or the biochemical and biophysical cues that orchestrate organoid morphogenesis. This review will examine recent advances in hNO technologies and culture strategies that promote reproducible in vitro morphogenesis and greater biomimicry in structure and function.more » « less
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McNulty, Jason D.; Marti-Figueroa, Carlos; Seipel, Frank; Plantz, Joshua Z.; Ellingham, Thomas; Duddleston, Lukas J.L.; Goris, Sebastian; Cox, Benjamin L.; Osswald, Tim A.; Turng, Lih-Sheng; et al (, Acta Biomaterialia)
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