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SELECTBIO Conferences Organ-on-a-Chip & Tissue-on-a-Chip Europe 2019


Human Vascular Microphysiological Systems to Model Genetic and Acquired Diseases

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

Cardiovascular disease represents the major cause of death in much of the world today.  Current in vitro models fail to recapitulate the complex tissue architecture and 3D structure of in vivo vasculature and animal models do not accurately model disease states. To address these limitations, we developed an endothelialized tissue engineered blood vessel (eTEBV) microphysiological system. Small-diameter eTEBVs (400-800 µm) were prepared by plastic compression and perfused at physiological shear stresses for 1- 5 weeks. The eTEBVs expressed von Willebrand factor and demonstrated endothelial cell (EC)-specific release of nitric oxide (NO). Acute stimulation by TNFa transiently inhibited ACh-induced relaxation and was eliminated by pre-exposure of eTEBVs to therapeutic doses of statins. Treatment of eTEBVs with enzyme-modified low-density lipoprotein (eLDL) caused activation of endothelial cells and promoted monocyte adhesion and transmigration. Further, treatment of eTEBVs with 50 µg/mL of eLDL for 96 hours caused monocytes to become foam cells and inhibited vasoactivity, indicators of early atherosclerosis. Monocyte accumulation and foam cell formation were inhibited by addition of lovastatin with eLDL. Using smooth muscle cells (SMCs) and ECs derived from induced pluripotent stem cells (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 SMCs from individuals with HGPS show reduced vasoactivity, increased medial wall thickness, calcification and apoptosis in comparison to eTEBVs fabricated with SMCs from normal individuals or primary MSCs.  HGPS viECs aligned with flow but exhibited reduced function compared to normal controls.  Relative to eTEBVs with healthy cells, HGPS eTEBVs showed reduced function and markers of cardiovascular disease associated with the endothelium. HGPS eTEBVs exhibited a reduction in both vasoconstriction and vasodilation and HGPS viECs produced VCAM-1 and E-selectin in eTEBVs with either healthy or HGPS viSMCs.  HGPS eTEBV function could be restored by addition of a farnesyl transferase inhibitor with or without a rapamycin analog. These results indicate that we can use human eTEBVs to model a variety of diseases in vitro.

Add to Calendar ▼2019-06-18 00:00:002019-06-19 00:00:00Europe/LondonOrgan-on-a-Chip and Tissue-on-a-Chip Europe 2019Organ-on-a-Chip and Tissue-on-a-Chip Europe 2019 in Rotterdam, The NetherlandsRotterdam, The