(100d) A Human iPSC-Derived Brain-on-Chip to Model Delivery to the Brain

Achieving successful drug delivery to the brain requires testing in a model system that accurately recapitulates human brain structure and function. Specifically, the blood-brain barrier (BBB) exhibits low paracellular permeability and low transcellular transport, presenting a major bottleneck to brain delivery: over 98% of systemically administered brain therapeutics cannot cross the BBB. The BBB is a pervasive network of small-diameter (5-10 microns), thus high-curvature, vessels through the brain that is especially impenetrable in humans compared to other species. However, research to date often relies on 2D cellular models and/or animal models to assess BBB passage. As such, there exists an unmet and urgent need to build representative human brain models and clarify BBB traversal mechanisms. Enacting effective delivery pathways for brain-targeted therapeutics would be transformative for treating a broad range of neurological disorders.

To address this problem, we have engineered a 3D, microfluidics-based human stem cell-derived neurovascular unit. Induced pluripotent stem cells (iPSCs) are chosen as an advantageous basis for deriving this human cellular model with well-controlled and patient-specific genetic backgrounds. Major brain cell types are differentiated separately from iPSCs, encapsulated together in an engineered hydrogel, and subsequently self-assemble into 3D cellular architectures, including a fully integrated BBB with perfusable microvasculature with neighboring neuronal cell types. We characterize morphological features including vascular network parameters and neurovascular coupling, expression levels of key junctional and scaffolding proteins, and functional performance. We present our model in the context of simpler, alternative models and actual human brain parameters. Finally, we explore the ability of this system to model delivery in the human brain microenvironment. Taken together, this brain-on-chip model is uniquely suited to capture emergent tissue behaviors and study drug delivery to the brain, within the context of healthy vs. diseased states.