Human iPSC-based isogenic Blood Brain Barrier-on-Chip Platform enables Predictive Personalized Medicine applications

The blood brain barrier (BBB) is a multicellular neurovascular unit (NVU) in which pericytes, astrocytes, and neurons directly interact with brain microvascular endothelial cells (BMECs). In turn, BMECs form a specialized transporter barrier created by tight junctions and polarized efflux pumps. This fine-tuned cellular architecture permits the blood-to-central nervous system (CNS) passage of crucial nutrients and metabolic molecules while prohibiting the entry of deleterious factors and most drugs. Several neurological disorders involve BBB dysfunction, creating the need to understand BBB physiology and transport mechanisms in both health and disease. Marked differences in BBB substrate specificity and transporter activity across species limit the relevance of animal models. Therefore, a human-specific BBB model is crucial to study human diseases and for the discovery of new CNS permeable drugs.

Combining induced pluripotent stem cells (iPSC) and organ-on-chip technologies we developed a novel platform in which isogenic iPSC-derived iBMECs, astrocytes and neurons mimic human BBB functionality. iBMECs form a bioengineered vessel-like structure on the Organ-Chip and human astrocytes, pericytes and neurons form direct cell-to-cell interactions that mimic functionality at the level of an organ. The BBB-Chip exhibits physiologically relevant transendothelial electrical resistance and faithfully predicts BBB permeability of molecules. Whole human blood perfusion through the ‘blood vessel’ introduces another physiological interphase and demonstrates that iBMECs can protect spontaneously active neurons from cytotoxicity. Finally, genetic neurological disease modeling in the context of a functional organ reveals substrate transport variability across individual BBB, demonstrating the feasibility of this approach for predictive personalized medicine applications.