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

曲率诱导的二次流对具有生理流入的 3D 生物打印动脉模型中的机械转导和细胞生化信号传导的影响

基本信息

批准号：
1854415
负责人：
Michael Plesniak
金额：
$ 59.94万
依托单位：
George Washington University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1854415&HistoricalAwards=false
关键词：
Impact Curvature Induced Secondary Flows

项目摘要

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.

心脏病是美国和全世界男性和女性死亡的主要原因。除了对人类健康和生命损失的有害影响外，心血管疾病的经济影响在美国每年高达数百亿美元。与斑块形成相关的疾病，如动脉粥样硬化，是由与血液直接接触的动脉衬里细胞（内皮细胞）表达的生化信号触发的。众所周知，内皮细胞将生化信号传递到相邻的平滑肌细胞层，平滑肌细胞层控制动脉的特性，例如它们的硬度和血液流过的横截面积。这些生化信号部分是细胞对血液流过时所看到的机械力的反应。该项目的目的是研究这些细胞如何响应复杂的流动，例如发生在脉管系统的各个部分（例如弯曲，收缩，分支区域）的流动。该项目将根据实际的生理动脉，用内皮细胞生产新型的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仿自然生理学的血液流动的影响。这项研究将提高对现实条件下血流和动脉衬里细胞相互作用的理解。这种理解的进步最终可能转化为研究，以解决血管疾病的发病和进展。该项目还支持大量的外展活动，以提高在STEM领域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，沿着现实的生物反应器的开发，用于评估内皮细胞的反应。血管结构是复杂的，并且外部和内部几何形状（包括曲率、弯曲度和狭窄度）的组合导致在空间和时间上可变的流场。在第一个目标中，该研究将使用最先进的非侵入性激光技术，如粒子图像测速法，来测量患者特定血管几何形状中的整个流场。这将与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产生复杂的生理和病理生理流动，包括二次流动和狭窄引起的流动分离，这在自然血管结构中可见。在目标2中，患者特定的几何形状将通过包括内皮细胞的3D生物打印结构复制。这些逼真的生物反应器将用于通过细胞染色、免疫荧光成像和基因分析来测量这些容器在不同流动条件下的细胞生化信号。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液流动和由此产生的细胞反应之间的因果关系。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ultrasonic characterization and beyond: How to select a hydrogel for tissue engineering

超声波表征及其他：如何选择用于组织工程的水凝胶

DOI：
10.1121/10.0018760
发表时间：
2023
期刊：
The Journal of the Acoustical Society of America
影响因子：
0
作者：
Anderson, Megan S.;Bulusu, Kartik V.;Plesniak, Michael W.;Zhang, Lijie Grace;Sarkar, Kausik
通讯作者：
Sarkar, Kausik

In vitro and in vivo evaluation of 3D bioprinted small-diameter vasculature with smooth muscle and endothelium