02102nas a2200313   4500000000100000008004100001260001500042653001400057653001800071653002200089653001400111653001400125653001400139653002200153100001600175700001700191700001300208700001400221700002200235700001900257700001700276700001500293700001500308700001300323245009700336856007200433520126900505022001401774       2025                            d  c2025-03-1710adiffusion10adrug response10aElectrophysiology10aorganoids10aperfusion10ascaffolds10avascular networks1 aHongwei Cai1 aChunhui Tian1 aLei Chen1 aYang Yang1 aAlfred Xuyang Sun1 aKyle McCracken1 aJason Tchieu1 aMingxia Gu1 aKen Mackie1 aFeng Guo00aVascular network-inspired diffusible scaffolds for engineering functional midbrain organoids  uhttps://www.sciencedirect.com/science/article/pii/S19345909250004993 aOrganoids, 3D organ-like tissue cultures derived from stem cells, show promising potential for developmental biology, drug discovery, and regenerative medicine. However, the function and phenotype of current organoids, especially neural organoids, are still limited by insufficient diffusion of oxygen, nutrients, metabolites, signaling molecules, and drugs. Herein, we present vascular network-inspired diffusible (VID) scaffolds to mimic physiological diffusion physics for generating functional organoids and phenotyping their drug response. Specifically, the VID scaffolds, 3D-printed meshed tubular channel networks, successfully engineer human midbrain organoids almost without necrosis and hypoxia in commonly used well plates. Compared with conventional organoids, these engineered organoids develop more physiologically relevant features and functions, including midbrain-specific identity, oxygen metabolism, neuronal maturation, and network activity. Moreover, these engineered organoids also better recapitulate pharmacological responses, such as neural activity changes to fentanyl exposure, compared with conventional organoids with significant diffusion limits. This platform may provide insights for organoid development and therapeutic innovation.  a1934-5909