3D Inverse Modelling to Extract Local Hydrogel Remodelling and Stress Fiber Structure in Human Diseased Aortic Heart Valve Interstitial Cells

Direct assessment of three-dimensional (3D) cell single stress fiber (SF) structure and function remains technically challenging, due to the SF feature size falling well below the resolution of light microscopy. Therefore, computational approaches are needed to estimated the effective structures and contractile behavior of SFs in various states. Herein, we developed a 3D computational model of the contracting aortic heart valve interstitial cells (AVICs) embedded in 3D hydrogels to estimate their SF orientations and contractile forces. We first utilized our hydrogel inverse model to estimate the local hydrogel mechanical properties. Briefly, this approach produces a spatially varying hydrogel modulus field or profile that minimizes the error between the experimentally measured and simulated hydrogel deformations produced by a contracting AVIC. It was determined that AVICs both degrade the gel by enzymatic processes, as well as locally stiffen the gel by collagen deposition. Next, we developed two finite element based inverse models that utilized a single direction and dispersed orientation SF structures. Both models estimated that the greatest levels of SF forces occurred at AVIC protrusions. The second model estimated that the greatest levels of SF alignment occurred at AVIC protrusions while the AVIC midsection revealed less-aligned fibers. To the best of our knowledge, we report the first fully 3D computational contractile cell models which can predict locally varying stress fiber orientation and contractile force levels. Looking forward, these models may help us obtain an increased understanding of SF function at sub-cellular length-scales and can be incorporated into multi-scale models of tissue/organ function.