On-chip Modeling of Physiological and Pathological Blood-Brain Barrier Microenvironment for Studying Glial Responses to Neuroinflammation

The blood-brain barrier (BBB), a unique multicellular physical structure, maintains the central nervous system (CNS) homeostasis, and its disruption along with neurotoxic blood-derived molecules deposition is involved in various neurodegenerative diseases. Studying how the biological reactions of glial cells exacerbate the brain injury in the leaky BBB upon the insult of neuroinflammation is in urgent need for an in vitro physiologically relevant BBB-mimetic model. Here, we developed a microfluidic BBB chip model comprised of endothelial cells, astrocytes and microglia co-culture, which could innovatively recapitulate the physiological and pathological states when combined with particular hydrogels. Glia cells in the functional BBB with Matrigel as the matrix composition underwent significant activation by lipopolysaccharide (LPS) and specific aberrant protein aggregates stimulation, manifesting as astrocyte reactivity, higher microglial migration speed and the upregulated expression of activation marker, while the fibrin-mediated pathological extracellular microenvironment primed the glial cells to exhibit blunted responses to inflammatory irritation. We further verified the neuroprotective effect of the clinically sedative agent dexmedetomidine against neuroinflammation utilizing our BBB chip model. The BBB-on-a-chip may facilitate the elucidation of sophisticated cell-cell interactions in the progression of brain neurodegenerative diseases and the evaluation of preclinical drug efficacy.