Abstract
This work examines how mechanical signals affect the barrier function and stability of engineered human microvessels in microfluidic type I collagen gels. Constructs that were exposed to chronic low flow displayed high permeabilities to bovine serum albumin and 10 kDa dextran, numerous focal leaks, low size selectivity, and short lifespan of less than one week. Higher flows promoted barrier function and increased longevity; at the highest flows, the barrier function rivaled that observed in vivo, and all vessels survived to day 14. By studying the physiology of microvessels of different geometries, we established that shear stress and transmural pressure were the dominant mechanical signals that regulated barrier function and vascular stability, respectively. In microvessels that were exposed to high flow, elevation of intracellular cyclic AMP further increased the selectivity of the barrier and strongly suppressed cell proliferation. Computational models that incorporated stress dependence successfully predicted vascular phenotype. Our results indicate that the mechanical microenvironment plays a major role in the functionality and stability of engineered human microvessels in microfluidic collagen gels.