Human brain organoids, 3D brain tissue cultures derived from human pluripotent stem cells, hold promising potential in modeling
neuroinflammation for a variety of neurological diseases. However, challenges remain in generating standardized human brain organoids that can recapitulate key physiological features of a human brain. Here, we present tubular organoid-on-a-chip devices to generate better organoids and model
neuroinflammation. By employing 3D printed hollow mesh scaffolds, our device can be easily incorporated into multiwell-plates for reliable, scalable, and reproducible generation of tubular organoids. By introducing rocking flows through the tubular device channel, our device can perfuse nutrients and
oxygen to minimize organoid
necrosis and
hypoxia, and incorporate immune cells into organoids to model neuro-immune interactions. Compared with conventional protocols, our method increased neural progenitor proliferation and reduced heterogeneity of human brain organoids. As a proof-of-concept application, we applied this method to model the microglia-mediated
neuroinflammation after exposure to an
opioid receptor agonist. We found isogenic microglia were activated after exposure to an
opioid receptor agonist (
DAMGO) and transformed back to the homeostatic status with further treatment by a
cannabinoid receptor 2 (CB2) agonist (
LY2828360). Importantly, the activated microglia in tubular organoids had stronger
cytokine responses compared to those in 2D microglial cultures. Our tubular organoid device is simple, versatile, inexpensive, easy-to-use, and compatible with multiwell-plates, so it can be widely used in common research and clinical laboratory settings. This technology can be broadly used for basic and translational applications in inflammatory diseases including
substance use disorders, neural
diseases, autoimmune disorders, and
infectious diseases.