Engineering of Geometrically Organized Blood Vessels for Quantitative Assays on a Microfluidic Chip

Abstract

This thesis describes two microfluidic platforms that generate geometrically optimized microvessels for establishing various vascular biology related models. For vascular permeability assay, a novel microfluidic design was developed to form multiple perfusable 3D microvessels. The microvessels were formed by a natural angiogenic process and exhibit reliable functional barrier properties. The vessels acquired barrier function similar to those measured in vivo experiments with relatively low permeability coefficients for in vitro measurements. Manipulation of barrier properties by addition of agonists and growth factors, and the modeling of cancer microvessels were also demonstrated. For cancer angiogenesis and intravasation assay, a novel microfluidic design was developed to form a perfusable 3D microvessel with empty perivascular region, induced by natural vasculogenic process. For cancer angiogenesis assay, U87MG cancer cell line was introduced at the perivascular region. The cancer sprouts were observed three days after the cancer introduction, and could be attenuated by the treatment of anti-VEGF, bevacizumab. For cancer intravasation assay, MDA-MB-231 cancer cell line was introduced into the perivascular region and their migration toward the vessel wall was observed. Treatment of TNF-α showed disrupted morphology of the vessel junctions and increased portion of the intravasated cancer cells, agreeing with the previous in vivo studies. The models have potential to be applied for various studies, including cancer cell or leukocyte extravasation, mechanotransduction of endothelial cells to the intraluminal flow. The robustness and reproducibility of these microfluidic chip-based microvessels, combined with the feasibility for flexible customizable chip design, promise to make it a versatile device for future investigations in fundamental vascular biology as well as drug screening.