CAREER: Bridging Vascular Smooth Muscle Cell Stiffness into Arterial Mechanics to Advance the Mechanisms of Restenosis

1254095在美国，狭窄引起的心脏病和中风导致410万人长期身体残疾，特别是在老龄化人群中。支架植入术通过机械性扩张阻塞的动脉，恢复血流，从而缓解狭窄，已被广泛应用。支架植入术的主要并发症是支架内再狭窄（ISR），即细胞向管腔的负生长。急性ISR常加重狭窄引起的永久性残疾。已知支架诱导的异常负载导致血管细胞（特别是平滑肌细胞（VSMC））的适应不良生物反应，进而调节细胞外基质（ECM）组成、密度和结构，导致ISR。然而，很少有人知道血管平滑肌细胞刚度的变化，在响应支架诱导的负载和它的作用上的动脉的机械响应。PI的长期职业目标是从根本上了解细胞变化如何通过改变几何形状和材料特性（例如，刚度、孔隙率等）提高血管疾病的防治水平。作为实现这一目标的一步，本提案的研究目标是研究VSMC在各种载荷条件下的机械响应，并通过分层计算模拟结合体外细胞培养和拉伸组织试验确定其对支架植入后局部动脉硬化的影响。经验证的模型将捕获VSMC在支架诱导的动脉适应中的作用，并能够更好地理解和控制再狭窄。建议的工作的教育目标是确定和框架一个有效的跨学科的教学策略，培养学生通过工程方法解决医疗问题。PI将通过以下方式建立在她成功的教育活动基础上：招募和指导研究生/本科生和高中教师;开发跨学科课程;最后，领导针对中风康复患者，K-12学生和公众的创新外展计划。从根本上了解VSMC刚度的作用是制定有效的预防和治疗策略以降低再狭窄率的关键。该项目将弥合与再狭窄机制相关的知识差距。它将告知细胞动力学如何与组织行为相结合，从而导致动脉适应。将利用体外组织拉伸试验和细胞培养实验为计算模型和基准提供输入，以验证这些模型。这项研究将：提供了关于细胞对各种负荷的反应的新数据集;提供了利用细胞群和组织反应之间的耦合的新途径;并将提供一种新的思考再狭窄机制的方式。所提出的方法可以扩展到其他干预措施，包括血管移植和心脏瓣膜修复。拟议的研究是变革性的，因为它提供了一个创新的多尺度战略，以预测动脉适应，它有望使一个新的方法，进一步发展的微创医疗设备。更广泛的影响：通过完成拟议的工作所获得的知识将提供一个新的设计/评估平台的支架，并将促使在预防和治疗狭窄引起的残疾的变化。该项目将招募研究生和本科生，特别是女生。本研究纳入中风康复项目将导致先进的康复策略，中风所致残疾的人。丰富的本科课程将提高学生的学习，并准备训练有素的学生有关组织的性质。使用该大学荷兰计算中心的64个处理器获得的多尺度计算结果将向公众提供。将在内布拉斯加州立大学博物馆举行演讲，向K-12学生和公众介绍工程项目在解决医疗问题方面的相关性。高中科学教师将被招募到PI的实验室工作，努力将最新工程研究的例子注入他们的课程。将评估综合教育和研究活动的影响，并与社区分享。

1254095GuStenosis-induced heart disease and stroke result in 4.1 million long-term physical disabilities in the US, especially among aging populations. Stent implantation has been widely used to alleviate the stenosis by mechanically enlarging the blocked artery and restoring blood flow. A major complication of the stenting procedure is in-stent restenosis (ISR), the negative cell growth toward the lumen. Acute ISR often aggravates the stenosis-induced permanent disability. It was known that stent-induced abnormal loading leads to maladaptive biological responses of vascular cells, specifically smooth muscle cells (VSMC), which, in turn, regulates extracellular matrix (ECM) composition, density, and structure resulting in the ISR. However, very little is known about the changes of VSMC stiffness in response to stent-induced loadings and its role on the mechanical responses of the artery. This knowledge will be essential to advancing understanding of the detailed progression mechanism of restenosis.The PI's long-term career goal is to fundamentally understand how cellular changes are related to tissue remodeling by altering the geometry and material properties (e.g., stiffness, porosity, etc.) to improve the prevention and treatment of vascular diseases. As a step toward this goal, the research objective of this proposal is to investigate the mechanical responses of VSMC at various loading conditions and determine its impact on local arterial stiffening following the stent implantation through hierarchical computational simulations combined with in vitro cell culture and tensile tissue tests. The validated model will capture the role of VSMC on the stentinduced arterial adaptation and enable better understanding and control of restenosis. The educational goal of the proposed work is to identify and frame an effective interdisciplinary instructional strategy to train students in solving medical problems via engineering approaches. The PI will build on her successful education activities via the following: recruiting and mentoring graduate/undergraduate students and high school teachers; developing an interdisciplinary curriculum; and finally, leading innovative outreach programs for stroke rehabilitation patients, K-12 students, and the general public.Intellectual merit: Fundamental understanding the role of VSMC stiffness is the key to developing effective preventive and therapeutic strategies to reduce the restenosis rate. This project will bridge the knowledge gap related to the mechanisms of restenosis. It will inform how cellular dynamics are coupled with tissue behavior to result in arterial adaptation. In vitro tissue tensile testing and cell culture experiments will be utilized to provide inputs to computational models and benchmarks for validation of these models. This study will: provide new datasets on the cellular responses to various loads; provide new avenues to exploit the coupling between cell population and tissue response; and will provide a new way of thinking about mechanisms of restenosis. The proposed methodology could be extended to other interventions, including vascular grafting and heart valve repair. The proposed research is transformative in that it provides an innovative multi-scale strategy to predict the arterial adaptation; it is expected to enable a new methodology for further development of minimally-invasive medical devices.Broader impacts: The knowledge obtained by completing the proposed work will provide a new design/evaluation platform for stents and will prompt changes in the prevention and treatment of the stenosis-induced disability. Graduate and undergraduate students, especially women, will be recruited for this project. The integration of this research into a stroke rehabilitation project will lead to advanced rehabilitation strategies for persons with strokeinduced disabilities. An enriched undergraduate curriculum will improve student learning and prepare well-trained students regarding the tissue properties. Multiscale computational results obtained using 64 processors in the University's Holland Computing Center will be made available to the public. Presentations will be given at the University of Nebraska State Museum to inform K-12 students and the general public about the relevance of engineering programs in solving medical problems. High school science teachers will be recruited to work in the PI's lab in an effort to infuse their curricula with examples from the latest engineering research. The impact of integrated education and research activities will be evaluated and shared with the community.