Stenosis-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.