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.
摘要：
主动脉瓣间质细胞（AVIC）位于主动脉瓣的小叶组织内，并维持和重塑其细胞外基质成分。该过程的一部分是由潜在的应激纤维带来的AVIC收缩性的结果,其行为可以在各种疾病状态下改变。目前,直接研究致密小叶组织内的AVIC收缩行为具有挑战性。因此,光学透明的聚（乙二醇）水凝胶基质已用于通过3D牵引力显微镜（3DTFM）研究AVIC收缩性。然而,水凝胶的局部刚度难以直接测量,并且进一步被AVIC的重塑活性所混淆。水凝胶力学中的歧义可导致计算的细胞牵引中的大误差。在这里，我们开发了一种逆计算方法来估计AVIC诱导的水凝胶材料的重塑。通过测试问题验证了该模型，该问题包括实验测量的AVIC几何形状和包含未修改的规定模量场，加劲，和退化的地区。逆模型以高精度估计了地面实况数据集。当应用于通过3DTFM评估的AVIC时，该模型估计了中航工业附近显著变硬和退化的区域。我们观察到，硬化主要位于中航工业的突起处，可能是由免疫染色证实的胶原沉积的结果。退化在空间上更加均匀，并且存在于远离中航工业的区域，可能是酶活性的结果。展望未来,这种方法将允许更准确地计算中航工业收缩力水平。重要声明：主动脉瓣（AV），位于左心室和主动脉之间，防止逆流进入左心室.在AV组织内存在主动脉瓣间质细胞(AVIC)的常驻群体。并具有补充功能，恢复,重塑细胞外基质成分。目前,直接研究致密小叶组织内的AVIC收缩行为在技术上具有挑战性。因此,光学透明的水凝胶已用于通过3D牵引力显微镜研究AVIC收缩性。在这里，我们开发了一种评估AVIC诱导的水凝胶重塑的方法。该方法能够准确估计中航工业引起的显著硬化和退化区域，可以更深入地了解AVIC对疾病状况的反应。
