Impact of Curvature-Induced Secondary Flows on Mechanotransduction and Cell Biochemical Signaling in 3D Bioprinted Artery Models with Physiological Inflow

心脏病是美国和全世界男性和女性的主要死因。除了对人类健康和生命损失的有害影响外，心血管疾病在美国每年造成的经济影响高达数百亿美元。与斑块形成相关的疾病，如动脉粥样硬化，是由动脉衬里细胞直接与血液接触的内皮细胞表达的生化信号引发的。众所周知，内皮细胞将生化信号传递给邻近的平滑肌细胞层，这些细胞层控制着动脉的特性，如动脉的硬度和血液流经的横截面积。这些生化信号在一定程度上是细胞对血液流过时所看到的机械力的反应。这个项目的目标是研究这些细胞如何对复杂的流动做出反应，例如发生在血管系统不同部分的那些流动(例如，曲率区域、收缩、分支)。该项目将以实际的生理动脉为基础，用内皮细胞制作新型的3D生物打印血管模型。然后，这些逼真的生物反应器将受到模拟自然生理的血液流动的影响。这项研究将加深对现实条件下血流和动脉内衬细胞相互作用的理解。这种认识上的进步最终可能转化为研究血管疾病的发生和发展。该项目还支持大量的外展活动，以加强STEM领域中代表性不足的学生的参与。该项目包括实验和计算建模的结合，以及用于评估内皮反应的现实生物反应器的开发。血管结构是复杂的，外部和内部几何结构的组合，包括曲率、弯曲和狭窄，导致流场在空间和时间上都是可变的。在第一个目标中，这项研究将使用最先进的、基于非侵入性的激光技术，如粒子图像测速仪，来测量患者特定血管几何形状的整个流场。这将与通过计算模拟确定的壁面剪应力分布的评估相结合。这些逼真的几何形状将创建复杂的生理和病理生理流动，包括二次流动和狭窄诱导的流动分离，这在自然血管结构中可以看到。在目标2中，将通过包括内皮细胞的3D生物打印结构来复制患者特定的几何图形。这些真实的生物反应器将通过细胞染色、免疫荧光成像和基因分析来测量不同流动条件下这些血管内的细胞生化信号。通过整合来自不同学科的这两种方法，该项目将能够检查复杂的血流和由此产生的细胞反应之间的因果关系。这一奖项反映了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。

Heart disease is the leading cause of death for men and women in the United States and throughout the world. In addition to the detrimental effects on human health and loss of life, the economic impact of cardiovascular diseases is tens of billions of dollars annually in the US. Diseases associated with plaque formation, such as atherosclerosis, are triggered by the biochemical signals expressed by the arterial lining cells in direct contact with the blood, the endothelial cells. It is known that the endothelial cells transmit biochemical signals to adjacent smooth muscle cell layers that control the properties of the arteries, such as their stiffness and cross-sectional area through which the blood flows. These biochemical signals are, in part, the response of the cells to the mechanical forces that they see as the blood flows past. The objective of this project is to study how these cells respond to complex flows, such as those that occur in various parts of the vasculature (e.g. regions of curvature, constrictions, branching). This project will produce novel, 3D bioprinted blood vessel models with endothelial cells based on actual physiological arteries. These realistic bioreactors will then be subjected to blood flow that mimics the natural physiology. This study will improve the understanding of the interactions of blood flow and arterial lining cells under realistic conditions. This advancement in understanding may eventually translate to research to address the onset and progression of vascular diseases. The project also supports substantial outreach to enhance the participation of underrepresented students in STEM fields.This project includes a combination of experimental and computational modeling along with the development of realistic bioreactors for the assessment of endothelial response. Vascular structures are complex, and the combination of external and internal geometry, including curvature, tortuosity, and stenoses, leads to flow fields that are variable in both space and time. In the first aim, the research will use state-of-the-art, non-invasive laser-based techniques, such as Particle Image Velocimetry, to measure the entire flow field in patient-specific vascular geometries. This will be combined with the assessment of wall shear stress distributions determined from computational simulations. These realistic geometries will create the complex physiological and pathophysiological flows, including secondary flows and stenosis-induced flow separations, that are seen in natural vascular structures. In aim 2, the patient-specific geometries will be replicated through 3D bioprinted structures that include endothelial cells. These realistic bioreactors will be used to measure cellular biochemical signaling within these vessels under different flow conditions through cell staining, immunofluorescence imaging, and gene analysis. By integrating these two approaches from different disciplines, the project will be able to examine the cause and effect between the complex blood flow and the resulting cell response.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.