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

循环系统有一项艰巨的任务，那就是将氧气和营养物质分配给体内的每个细胞。血液在组织细胞内的分布是在毛细血管中进行的，毛细血管是体内最小的血管。毛细管床通常保持稳定，但当有特殊的氧气需求时，可以在局部改装。从先前存在的血管产生新血管的过程称为血管生成。在人类，血管生成发生在愈合过程中，这是有益的，也发生在癌症肿瘤的生长过程中。在癌症中，恶性细胞迅速增殖，造成局部缺氧(低氧浓度)。在低氧条件下，癌细胞释放生长因子到达附近的血管并触发血管生成。通过招募新血管，肿瘤可以继续生长。肿瘤诱导的血管生成受基于分子运动的相互交织的分子机制的支配，这些分子被称为肿瘤血管生成因子，在组织内。虽然调控血管生成的生化信号通路已经被广泛研究，但生物物理信号的作用仍然知之甚少。通过引入一种独特的计算方法，该项目将研究流体流动对肿瘤血管生成因子运输的影响，以及这些分子的联合扩散和基于流动的运动如何改变血管生成。这项工作发生在工程学和生物学的交界处，其影响将应用于肿瘤药物输送、了解肿瘤转移，甚至在再生医学的组织工程结构中开发供血的毛细血管。更广泛的研究影响将得到推广和教育活动的补充，包括开发虚拟现实动画来模拟毛细血管中的血液流动，可以向年轻学生展示这些动画，以激发他们对科学计算和生理学的兴趣。该项目旨在开发一种新颖的相场血管生成模型，该模型将与高保真流体流动理论相结合，该理论解释了在时间演变的毛细血管网络上的血管内、血管内和血管外流动。这将通过模拟的3个焦点来实现。首先，将探讨可溶性与基质结合的血管内皮生长因子的作用，以解释关于血管内皮生长因子转运与毛细血管发育关系的相互矛盾的实验证据。其次，将模拟体内的间质流动，以阐明血管生成和间质流动的双向耦合动力学所涉及的机制。最后，将模拟体内类间质血流对肿瘤血管生成的影响，并将其与先前确定的实验结果进行比较。在这项科学工作的同时，将在流体力学的机械工程本科课程中引入生物流体模块，并将本科生整合到计算模型研究中。除了直接参与研究，本科生还将参与使用Oculus Rift(TM)开发3D虚拟现实模拟。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.