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SELECTBIO Conferences Organ-on-a-Chip, Tissue-on-a-Chip Europe 2018


Human Vascular Microphysiological System Models for Drug Testing and Disease Modeling

George Truskey, R. Eugene and Susie E. Goodson Professor of Biomedical Engineering, Duke University

We developed an endothelialized tissue engineered blood vessel (eTEBV) microphysiological system by rapid generation of small-diameter vessels (400-800 ┬Ám) by plastic compression. TEBVs were mechanically strong enough to allow endothelialization and perfusion at physiological shear stresses immediately after fabrication.  eTEBVs perfused at physiological shear stresses for 1- 5 weeks expressed von Willebrand factor (vWF) and demonstrated EC-specific release of NO, indicating a confluent layer of ECs. After 1-5 weeks of perfusion, eTEBVs exhibited dose-dependent contraction and relaxation following exposure to phenylephrine and acetylcholine (ACh), respectively. In contrast, TEBVs without ECs or eTEBVs pre-treated with the NO synthase inhibitor L-NG-Nitroarginine methyl ester underwent vasoconstriction in response to ACh consistent with vasodilation by EC release of NO. TEBVs elicited reversible activation following acute stimulation by TNFa which transiently inhibited ACh-induced relaxation, and was eliminated by pre-exposure of eTEBVs to therapeutic doses of statins. TNFa treatment also promoted monocyte adhesion and transmigration.  Using smooth muscle cells and endothelial cells derived from iPSCs, we produced a functional eTEBV model of Hutchison-Gilford Progeria Syndrome (HGPS), a rare, accelerated aging disorder caused by an altered form of the lamin A (LMNA) gene termed progerin.  eTEBVs fabricated with smooth muscle cells from individuals with HGPS show reduced vasoactivity, increased medial wall thickness, increased calcification and apoptosis in comparison to eTEBVs fabricated with smooth muscle cells from normal individuals or primary MSCs.  In addition, treatment with the rapamycin analog, RAD001, increased HGPS TEBV vasoactivity and reduces some disease symptoms.  These results indicate that we can use human eTEBVs to model diseases in vitro.

This work was supported by NIH grants 4UH3TR000505, 1UG3TR002142, and 1R01HL138252 from NIAMS, NCATS, NHLBI and the NIH Common Fund for the Microphysiological Systems Initiative.

Add to Calendar ▼2018-06-05 00:00:002018-06-06 00:00:00Europe/LondonOrgan-on-a-Chip, Tissue-on-a-Chip Europe 2018Organ-on-a-Chip, Tissue-on-a-Chip Europe 2018 in Rotterdam, The NetherlandsRotterdam, The