Unveiling the Role of Interstitial Flow in Angiogenesis through Phase-Field Simulations

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The circulatory system has the daunting task of distributing oxygen and nutrients to every cell in the body. The distribution of blood within the cells of a tissue occurs in capillaries, the smallest vessels in the body. The capillary beds usually remain stable, but they can be locally remodeled when there are special needs for oxygen. The process whereby new blood vessels are created from pre-existing ones is called angiogenesis. In humans, angiogenesis happens during would healing, which is beneficial, as well as during the growth of cancerous tumors. In cancer, malignant cells proliferate quickly, which creates local hypoxia (low oxygen concentration). Under hypoxic conditions, cancer cells release growth factors that reach the nearby vessels and trigger angiogenesis. By recruiting new blood vessels, tumors can continue their growth. Tumor-induced angiogenesis is governed by intertwined molecular mechanisms based on the movement of molecules, known as tumor angiogenic factors, within the tissue. While the biochemical signaling pathways that regulate angiogenesis have been widely investigated, the role of biophysical cues remains poorly understood. By introducing a unique computational method, this project will study the impact of fluid flow on the transport of tumor angiogenic factors and how the combined diffusion and flow-based movement of these molecules changes angiogenesis. The impact of this work, which occurs at the interface of engineering and biology, will be seen in applications to tumor drug delivery, understanding tumor metastasis, and even the development of capillaries to supply blood in tissue engineered structures for regenerative medicine. The research broader impacts will be complemented by outreach and educational activities, including the development of virtual reality animations that simulate blood flow in capillaries that can be shown to younger students to excite them about scientific computing as well as physiology.This project is designed to develop a novel, phase-field model of angiogenesis that will be coupled with high-fidelity fluid flow theory that accounts for intravascular, transvascular and extravascular flow on a time-evolving capillary network. This will be accomplished through 3 focuses for the simulations. First, the role of soluble as compared to matrix-bound VEGF (vascular endothelial growth factor) will be explored to explain the contradictory experimental evidence regarding the relationship between VEGF transport and capillary development. Second, in vivo-like interstitial flow will be modeled to elucidate the mechanisms involved with two-way coupled dynamics of angiogenesis and interstitial flow. Finally, the effect of in vivo-like interstitial flow on tumor angiogenesis will be modeled and compared to previously determined experimental results. The scientific work will be accompanied by the introduction of biofluid modules into a mechanical engineering undergraduate course in fluid mechanics as well as the integration of undergraduate students into the computational modeling research. In addition to particpating directly in the research, the undergrads will be involved with developing 3D virtual reality simulations using Oculus Rift(TM).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.