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Simulating The 3d Contractile Function Of The Aortic Heart Valve Interstitial Cell
Alex Khang1, John Steinman1, Xinzeng Feng1, Chiara Camillo2, Giovanni Ferrari2, Michael S. Sacks1.
1The University of Texas at Austin, Austin, TX, USA, 2Columbia University, New York City, NY, USA.

OBJECTIVE:
The aortic valve interstitial cell (AVIC) oversees extracellular matrix (ECM) maintenance and turnover within the aortic valve (AV) tissues and become activated in disease. AVIC activation is characterized by increased ECM production, remodeling, and contractility via expression of alpha-smooth muscle actin (aSMA) stress fibers. The individual aSMA fibers produce physical forces that cannot be directly measured but rather computed. This can be done by simulating AVIC contraction in tissue-emulating 3D PEG hydrogel environments. The goal of this study was to develop a 3D simulation to extract AVIC stress fiber forces to investigate contractile differences between AVICs from structurally normal and bicuspid AVs. METHODS:
Human AVICs from normal and bicuspid AVs were extracted (Fig. 1A) and seeded within 3D hydrogels. Confocal microscopy was used to image the AVIC sub-cellular structures and to discern their contractile behavior and shape via 3D traction force microscopy (Fig. 1B). A finite-element model of the AVIC was developed (Fig. 1C) to investigate differences in contraction strength of the underlying stress fibers between healthy and diseased AVICs.

RESULTS:
AVICs from both groups displayed complex shapes containing multiple protrusions that produced displacement fields with regions of contraction and expansion. We note that AVICs derived from bicuspid AVs produced lower levels of displacement, net cellular force, and total strain energy than AVICs from normal AVs. These differences were captured by the model, which revealed a lower contraction strength per unit stress fiber in bicuspid AVICs.
CONCLUSIONS:
Significant differences in contractile behaviors exist between healthy and diseased AVICs, which suggests that future treatment options for AV diseases should potentially target cell-level responses. Our future work will incorporate our AVIC model within a multi-scale model of the heart to better understand the interrelationship between organ-level stimuli and AVIC pathophysiology.


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