The broader impact of this Small Business Technology Transfer (STTR) Phase I project will be to refine clinical injury thresholds of the blood-brain barrier (BBB) resulting from traumatic brain injury (TBI) and other neurological diseases. This novel platform is a flexible BBB-based â€œorgan-on-chipâ€ to allow for animal-free testing of cell response and drug treatments for TBI. Organ-on-chips are microfluidic cell culture chips that simulate tissues, organs, or organ systems. In general, improvements in the design and manufacture of organ-on-chips can eventually replace animal models, especially rodent models, as subjects in preclinical drug evaluations. The proposed technology can support future applications in drug development for BBB breakdown, or be used as a platform to test or engineer drugs for transport across the BBB. Finally, the resulting data can be used for modeling transport, injury, and BBB dysfunction.
The proposed project will advance a novel technology for studying long-term implications of TBI and other neurological diseases. The BBB is a highly selective semipermeable membrane that separates brain tissue and the vascular system, and it can be damaged when trauma disrupts its structural, physiological and functional integrity. However, the role of TBI-mediated mechanics (magnitude, deceleration, impact frequency) on the modulation of BBB structure and function is poorly known. To date few organ-on-chip models enablee this type of study, and none incorporates TBI as an input variable. The proposed technology provides a TBI-like mechanical insult to the chipâ€™s BBB component, a flexible, porous membrane that separates microvascular endothelial cells and astrocytes. The proposed technology can quantify (1) transendothelial electrical resistance across the membrane, (2) BBB permeability, (3) epithelial barrier coefficient, (4) tight junction formation, and (5) cell phenotype, all of which are expected to change during and after TBI. This project will design a more robust electrode system to reproducibly measure transendothelial electrical resistance through micro-dispensing techniques used to 3D-print conductive ink directly onto the BBB membrane.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.