Development of a novel In vitro blood brain barrier model for the evaluation of nanomedicines

Blood brain barrier;Organ on a chip

Hovell, Candice Megan ; Kim, YongTae Taite, Lakeshia Barabino, Gilda Dixon, Brandon Lu, Hang Botchwey, Edward Vazquez, Maribel Biomedical Engineering (Joint GT/Emory Department) ; Kim, YongTae

University:Georgia Institute of Technology

Department:Biomedical Engineering (Joint GT/Emory Department)

关键词: Blood brain barrier;    Organ on a chip;   

Others  :  https://smartech.gatech.edu/bitstream/1853/60667/1/HOVELL-DISSERTATION-2017.pdf

美国|英语

来源: SMARTech Repository

【 摘 要 】

In this work, we present a novel microfluidic lumen system of the BBB (MLS-BBB) for the evaluation of multifunctional nanomedicines engineered for the treatment of medulloblastoma. Our MLS-BBB is designed to co-culture human astrocytes (HA) and human brain vascular pericytes (HBVP) around a cylindrical lumen of human brain microvascular endothelial cells (HBMEC) within a 3D hydrogel system tuned to mimic the properties of brain extracellular matrix (ECM). Our MLS-BBB facilitates the administration of tunable shear rates to a lumen of endothelial cells in direct contact with supporting astrocyte and pericyte cells within a hydrogel system optimized to facilitate the appropriate culture of astrocytes, and is to our knowledge, the first model to do so. We employed high throughput qPCR techniques to simultaneously analyze expression of 85 BBB relevant endothelial specializations such as junctional proteins (ZO-1, Claudins, JAMs, etc.), specialized transporters (GLUT-1, CAT1, TfR, etc.) and drug resistant proteins (PgP, ABCC1, ABCC4, etc.). Our results indicate that our system provides a marked increase in physiological relevance relative to transwell culture systems. Our model was further validated through comparison to BBB spheroids, by examination of model response to perturbations of the optimized ECM composition, and examination of response to the administration of TNFα, an inflammatory cytokine. Our model is currently being employed in parallel with traditional transwell systems and ex vivo brain slice cultures in the preliminary evaluation of a novel nanomedicine designed for the treatment of sonic hedgehog driven (SSH) medulloblastoma to evaluate its functional utility in such studies. The ultimate goal of organ-on-a-chip model development is eventual adaptation by the community for preclinical assessment of novel drug compounds. While our MLS-BBB could be improved in several ways, including modification to a high throughout design, by combining comprehensive characterization with an assessment of functional utility relative to standard in vitro controls, we believe our work constitutes a significant step towards the realization of this goal.