Jacquelyn Ann Brown, Monika G Judge, David K Schaffer, Dillon C Gavlock, Armando Irizarry Rovira, Steven K Engle, Thomas K Baker, John P Wikswo
Clinical drug attrition has not improved in the last six decades, peaking at ∼91% in the 2000s-2010s, with most failures linked to biological factors. These findings suggest that prevailing preclinical approaches - many of which heavily rely on animal models - often have limited ability to predict clinical outcomes and highlight the urgent need for more predictive, human-relevant NAMs.
BACKGROUND: It has long been established that the central nervous system (CNS) is a highly privileged space, with the blood-brain barrier (BBB) acting as the gatekeeper that allows or denies access to the brain by nutrients, drugs, and toxins. The BBB, however, is not the only barrier at play. The barrier between blood and cerebrospinal fluid (CSF) also has a critical role in guarding and feeding the CNS, but despite its importance, the blood-CSF barrier (BCSFB) remains relatively unexplored compared to the BBB, particularly with regard to models that do not rely on animals.
METHODS: Given the lack of physiologically relevant in vitro models and the divergence between humans and animal models, we created an organ-on-chip/microphysiological system to model the human BCSFB (hBCSFB) that can act as a new approach methodology (NAM) platform for interrogating physiological functions, evaluating drug delivery technologies and xenobiotic transport, and assessing the safety, efficacy, and mechanism of action of biopharmaceuticals.
RESULTS: By leveraging advanced microfluidic organ chip design and gravity perfusion, we have generated a hBCSFB organ chip that recapitulates many of the physiologically relevant characteristics of this barrier, including junctional protein expression, permeability less than 1.55e-5 cm/s, transcytosis that showed dose-dependent accumulation of 10%-35%, and selective transport that was both statistically significant (p ≤ 0.05) and reproducible.
CONCLUSION: Having achieved these benchmarks and validated their reproducibility, this work provides a useful in vitro system optimized for the qualitative and quantitative study of pharmacological and toxicological interactions involving the hBCSFB.