Cortical Organoid-on-a-Chip with Physiological Hypoxia for Investigating Tanshinone IIA-Induced Neural Differentiation.

Cortical organoids represent cutting-edge models for mimic human brain development during the early and even middle stage of pregnancy, while they often fail to recreate the complex microenvironmental factors, such as physiological hypoxia. Herein, to recapitulate fetal brain development, we propose a novel cortical organoid-on-a-chip with physiological hypoxia and further explore the effects of tanshinone IIA (Tan IIA) in neural differentiation. The microfluidic chip was designed with a micropillar array for the controlled and efficient generation of cortical organoids. With low oxygen, the generated cortical organoids could recapitulate key aspects of early-gestational human brain development. Compared to organoids in normoxic culturing condition, the promoted neurogenesis, synaptogenesis and neuronal maturation were observed in the present microsystem, suggesting the significance of physiological hypoxia in cortical development. Based on this model, we have found that Chinese herbal drug Tan IIA could promote neural differentiation and maturation, indicating its potential therapeutic effects on neurodevelopmental disorders as well as congenital neuropsychiatric diseases. These results indicate that the proposed biomimetic cortical organoid-on-a-chip model with physiological hypoxia can offer a promising platform to simulate prenatal environment, explore brain development, and screen natural neuroactive components.