Suspension Culture With Uniform Shear Stress in Brain Organoids‐on‐a‐Chip for Modelling Alzheimer's Disease

ABSTRACT Research on Alzheimer's disease (AD) has been hindered by the absence of customizable and physiologically relevant in vitro brain models. Although human induced pluripotent stem cell‐derived brain organoids (BOs) are beginning to shift the way it is study neurodegenerative disease, BOs notoriously suffer from the limited maturation and ‘batch effect’. Due to the lack of vascular systems, suspension cultures often maintained with spinning bioreactors allow for the growth of BOs with large volumes. But spinning bioreactors are limited in size and throughput, as well as in the uneven distribution of shear stress. Here, through computer simulation, suspension culture is achieved by constructing a brain‐organoids‐on‐a‐chip (BOoC), which allows adequate oxygenation and nutrient diffusion, facilitating the long‐term culture and high maturity of BOs. The uniformly distributed and precisely controllable fluid shear stress in the chip, accompanied by the uniform microstructural units, provided bionic physiological clues for the homogeneous development of organoids. Then the suspension culture design physiologically mimics serum exposure, induced the elevated amyloid β aggregation and tau phosphorylation in BOs, as well as neuronal reduction and synaptic loss, which recapitulate the key pathological features of AD. This BOoC platform provides a microphysiological system for generating highly mature and homogeneous BOs and simulating the pathological process of AD in vitro.