Normalization of microvascular physiology in engineered microvessels via cyclic adenosine monophosphate supplementation and artificial lymphatic drainage
Wong, Ho Ki Keith
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The generation of a functional microcirculation that can support timely and stable perfusion remains a major challenge in tissue engineering. To provide immediate perfusion, our research group has developed engineered microvessels in microfluidic collagen and fibrin scaffolds. This dissertation seeks to identify exogenous signals that can restore and normalize microvascular physiology in vitro. I found that supplementation of the second messenger cyclic AMP strongly enhanced microvascular barrier function and stabilized the vascular lumen for extended perfusion. These benefits were accompanied by a low cell turnover rate that is comparable to quiescent microvessels in vivo. Numerical modeling suggested a previously unrecognized consequence of vascular leakage in causing a rapid increase in interstitial pressure, which can decrease transmural pressure and may explain the correlation between vascular collapse and barrier dysfunction. Inspired by the physiological role of lymphatic vessels in interstitial fluid drainage, I hypothesized that a system of empty channels that provide an analogous drainage function could maintain high transmural pressures and thereby stabilize rnicrovessels. Single drainage channels stabilized vessels only locally and such effects depended on the distance to drainage and scaffold hydraulic conductivity, lending support to the idea that transmural pressure governs vascular stability. As a first step toward perfusing tissue constructs of a clinically relevant dimension, I engineered fibrin patches (0.8 cm by 0.9 cm) that contained an array of four perfusion vessels and an orthogonal array of drainage channels, and demonstrated their exceptional ability in sustaining long-term perfusion. In summary, this dissertation identified a set of tools to engineer in vivo-like rnicrovessels that may accelerate the development of thick and complex tissue constructs in vitro; furthermore, findings may suggest strategies to address certain vascular complications that are associated with tissue implantation, for instance edema and poor perfusion.
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