Core C: Computational and Experimental Biomechanical Assessment (CEBA)

Humphrey, Jay

Abstract

COMPUTATIONAL AND EXPERIMENTAL BIOMECHANICAL ASSESSMENT (CEBA) CORE C - PROJECT SUMMARY This Scientific Core will provide consistent and comprehensive biomechanical evaluation, both in vivo and in vitro, of the different mouse models used in this Program Project. First, mouse-specific aortic geometries will be determined using microCT whereas associated inlet and outlet flows and inlet pressures will be measured in vivo using ultrasound and Millar pressure catheters, respectively. Second, cylindrical specimens will be excised from the ascending, descending, suprarenal, and infrarenal segments of the aorta and subjected to novel, consistent, in vitro biomechanical phenotyping. Specifically, we will assess endothelial-dependent and independent vasodilatory capacity, compromised levels of induced biaxial smooth muscle cell contractility, and passive biaxial mechanical properties, and we will compare results across regions and groups using appropriate parametric and non-parametric statistics. Third, the biaxial material properties will be used to compute regional material and structural stiffnesses, energy storage, and layer-specific wall stresses, which in conjunction with the microCT and other in vivo data will inform unique fluid-solid-interaction computational simulations that can assess effects of altered geometry and wall properties on the micro-mechanical environment to which each of the primary cell types is exposed (e.g., endothelial shear stresses and smooth muscle and fibroblast intramural stress). These results, in turn, will be provided to each of the four Projects within the overall Program Project to enable correlations of mechanical stimuli with results from the myriad biological assays used in each project. In this way, collectively we will be able to evaluate, for the first time, critical roles of cellular mechanosensing and mechanoregulation of the extracellular matrix that endows the thoracic aorta with its compliance and strength and when compromised results in the loss of structural integrity that manifests as a potentially lethal thoracic aortic aneurysm.

Public Health Relevance

Mounting evidence reveals that thoracic aortic aneurysms and dissections ? which afflict young and old individuals alike ? are responsible for even greater disability and death than long thought. Recent discoveries in genetics point to a novel mechano-biological mechanism by which these conditions arise and progress. This project will provide unique data that will enable the discovery of these underlying mechanisms and the translation of this knowledge into novel, lifesaving treatments.