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Open Access Publications from the University of California

Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UC Irvine Electronic Theses and Dissertations (2014)

Treatments for cancer remain elusive due, in large part, to the dynamic and unstable genome of most cancer cells. More recently it has become evident that tumor growth and progression to metastasis depends on the ability to recruit normal cells, such as endothelial cells, fibroblasts, as key accomplices. These observations suggest that selective targeting of normal cells, which have a stable genome, could be an effective alternative or complimentary approach in the overall management of the disease. Understanding of such relationship is key for the design of anti-metastatic therapeutics. However, much of the data reported in this field has been performed in xenograft models and/or 2D cultures; which are limited by the number of controllable variables, extrapolation to human tumor physiology, and not amenable for a high-throughput design. This work aims to address the role of the tumor microenvironment using a novel in vitro platform that combines microfluidic and tissue engineering technology to create a 3D tumor microarray in which the tumors receive their nutrients through perfused human microcirculation. This model is capable of replicating the physiology of the in vivo tumor microenvironment; thus providing relevant physiological results. Most importantly, the impact of creating an in vitro 3D metastasis model with perfused human capillary bed could significantly enhance high-throughput anti-metastatic drug screening.

    Cover page: Microfluidic Tools to Recapitulate the Tumor Microenvironment
    • Article
    • Peer Reviewed
    UC Davis Previously Published Works (2017)
    Convective transport can significantly distort spatial concentration gradients. Interstitial flow is ubiquitous throughout living tissue, but our understanding of how interstitial flow affects concentration gradients in biological processes is limited. Interstitial flow is of particular interest for angiogenesis because pathological and physiological angiogenesis is associated with altered interstitial flow, and both interstitial flow and morphogen gradients (e.g., vascular endothelial growth factor, VEGF) can potentially stimulate and guide new blood vessel growth. We designed an in vitro microfluidic platform to simulate 3D angiogenesis in a tissue microenvironment that precisely controls interstitial flow and spatial morphogen gradients. The microvascular tissue was developed from endothelial colony forming cell-derived endothelial cells extracted from cord blood and stromal fibroblasts in a fibrin extracellular matrix. Pressure in the microfluidic lines was manipulated to control the interstitial flow. A mathematical model of mass and momentum transport, and experimental studies with fluorescently labeled dextran were performed to validate the platform. Our data demonstrate that at physiological interstitial flow (0.1-10 μm/s), morphogen gradients were eliminated within hours, and angiogenesis demonstrated a striking bias in the opposite direction of interstitial flow. The interstitial flow-directed angiogenesis was dependent on the presence of VEGF, and the effect was mediated by αvβ3 integrin. We conclude that under physiological conditions, growth factors such as VEGF and fluid forces work together to initiate and spatially guide angiogenesis.
      Cover page: Low levels of physiological interstitial flow eliminate morphogen gradients and guide angiogenesis.
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