Estimation of aortic valve interstitial cell-induced 3D remodeling of poly(ethylene glycol) hydrogel environments using an inverse finite element approach

Abstract

Aortic valve interstitial cells (AVICs) reside within the leaflet tissues of the aortic valve and maintain and remodel its extracellular matrix components. Part of this process is a result of AVIC contractility brought about by underlying stress fibers whose behaviors can change in various disease states. Currently, it is challenging to directly investigate AVIC contractile behaviors within dense leaflet tissues. As a result, optically clear poly (ethylene glycol) hydrogel matrices have been used to study AVIC contractility via 3D traction force microscopy (3DTFM). However, the local stiffness of the hydrogel is difficult to measure directly and is further confounded by the remodeling activity of the AVIC. Ambiguity in hydrogel mechanics can lead to large errors in computed cellular tractions. Herein, we developed an inverse computational approach to estimate AVIC-induced remodeling of the hydrogel material. The model was validated with test problems comprised of an experimentally measured AVIC geometry and prescribed modulus fields containing unmodified, stiffened, and degraded regions. The inverse model estimated the ground truth data sets with high accuracy. When applied to AVICs assessed via 3DTFM, the model estimated regions of significant stiffening and degradation in the vicinity of the AVIC. We observed that stiffening was largely localized at AVIC protrusions, likely a result of collagen deposition as confirmed by immunostaining. Degradation was more spatially uniform and present in regions further away from the AVIC, likely a result of enzymatic activity. Looking forward, this approach will allow for more accurate computation of AVIC contractile force levels. STATEMENT OF SIGNIFICANCE: The aortic valve (AV), positioned between the left ventricle and the aorta, prevents retrograde flow into the left ventricle. Within the AV tissues reside a resident population of aortic valve interstitial cells (AVICs) that replenish, restore, and remodel extracellular matrix components. Currently, it is technically challenging to directly investigate AVIC contractile behaviors within the dense leaflet tissues. As a result, optically clear hydrogels have been used to study AVIC contractility through means of 3D traction force microscopy. Herein, we developed a method to estimate AVIC-induced remodeling of PEG hydrogels. This method was able to accurately estimate regions of significant stiffening and degradation induced by the AVIC and allows a deeper understanding of AVIC remodeling activity, which can differ in normal and disease conditions.

Keywords: 3D traction force microscopy; Adjoint method; Aortic valve interstitial cell; Collagen deposition; Computational modeling; Degradation; Hydrogel; Inverse modeling; Stiffening.