CAREER: Remodeling Drives Spatial Variations in Soft Tissue Mechanics and Multiscale Structure

About This Grant

This award supports research that studies how tissues modify their structure over time and how these changes are influenced by mechanical loading. The research focuses on the aortic valve leaflet, a vital part of the heart that opens and closes to control blood flow. The cells in the leaflet are constantly remodeling: building, breaking down, and rearranging the supportive material around them—based on various stimuli, including mechanical loading. However, these structural changes also affect the mechanical loading on the leaflet, creating a feedback loop that is not yet fully understood. In calcific valve disease, this process leads to the thickening and hardening of the leaflet, preventing it from opening properly. This increases the workload on the heart, ultimately leading to heart failure. To investigate this feedback loop, this project will: 1) Develop a new method to measure how the material properties of the leaflet vary across its surface and over time and 2) Use advanced imaging techniques to study the leaflet's structure at different scales, particularly around small calcium deposits (microcalcifications) that stiffen the valve and reduce its function. The developed technology and research findings will also enable future studies aimed at slowing, stopping, or even reversing the formation and growth of microcalcifications. This work will help to elucidate the role of mechanics during aortic valve leaflet remodeling. Remodeling is a continuous process: as cells synthesize, degrade, and rearrange their local extracellular matrix, its load-bearing properties change, which in turn alters local mechanical stimuli. This study will be the first to quantify the temporal changes in the regional mechanics and structure of individual aortic valve leaflets during culture. To do this the research team will develop a novel, structure-informed nonlinear anisotropic inverse mechanics method that quantifies spatially variable material properties from biaxial testing data. The team will also determine the multiscale structure of the leaflets at multiple time points during culture using quantitative polarized light imaging, a mesoscale imaging technique, to guide the application of microscale imaging. This will provide a detailed characterization of the extracellular matrix structure at and around microcalcifications as they form and grow. The spatial and temporal information collected in this study will enable to better understand the feedback mechanisms between leaflet mechanics and remodeling. Additionally, because this technology enables both spatial and temporal studies, results will be useful for future testing hypothesis concerning the underlying mechanisms of microcalcification formation and evaluating potential treatments. 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.