Biomimetic Blood vessel Model to elucidate Physicochemical Mediators of Tumor Angiogenesis

We are developing microfluidic cell cultures in remodelable hydrogel scaffolds to recapitulate tumor angiogenesis in a physiologically relevant, spatiotemporally-controlled in vitro system. Despite significant progress in vascular research, many of the parameters contributing to aberrant endothelial function remain unclear. To address these questions, we micro-tissue engineered biomimetic blood vessels in dense collagen scaffolds and subjected them to gradients of tumor-secreted soluble factors. This platform helped illuminate hitherto underappreciated biophysicochemical mediators of tumor angiogenesis, including endothelial cell density, vessel geometry, and morphogen gradients. Summary of Research: The recruitment of vasculature for transport of nutrients and waste is a bona fide hallmark capability in tumor pathogenesis and constitutes an enduring target for therapeutic intervention. However, highly anticipated anti-angiogenic drugs, such as Avastin®, demonstrated underwhelming success in clinical implementation. The disparity between preclinical results and actual patient benefit indicates a need for improved assays that are capable of accurately mimicking the physiological complexities of cancer, while selectively delineating these cues with appropriate physicochemical control and spatiotemporal resolution. By precise definition of salient biological features, microfabricated culture systems afford the independent interrogation of specific biophysical characteristics of the tumor microenvironment [1]. We exploited these technologies to explore the process of tumor angiogenesis in tissue-engineered blood vessels. Specifically, we used softlithography to pattern microchannels in natural extracellular matrix scaffolds. A three-channel design was used to generate stable chemical gradients across a central endothelialized vessel (Figure 1). Human umbilical vein endothelial cells (HUVEC) formed a functional, confluent vessel (Figure 2), Figure 1, above: Cut-out view of micropatterned, type I collagen-based platform for stable, gravitydriven perfusion and gradient generation across a fullyenclosed, biomimetic blood vessel. Inset shows channel cross-section with endothelialized center channel and morphogen concentrations [C1] and [C2] in the source and sink channels, respectively. Figure 2, left: Confocal image of quiescent, confluent endothelium, showing maximum intensity projection along the z-axis. BIOLOGICAL APPLICATIONS 21 2011-2012 CNF RESEARCH ACCOMPLISHMENTS B