Adherent cells are generally able to reorient in response to cyclic strain. In three-dimensional tissues, however, extracellular collagen can affect this cellular response. In this study, a computational model able to predict the combined effects of mechanical stimuli and collagen on cellular (re)orientation was developed. In particular, a recently proposed computational model (which only accounts for mechanical stimuli) was extended by considering two hypotheses on how collagen influences cellular (re)orientation: collagen contributes to cell alignment by providing topographical cues (contact guidance); or collagen causes a spatial obstruction for cellular reorientation (steric hindrance). In addition, we developed an evolution law to predict cell-induced collagen realignment. The hypotheses were tested by simulating bi- or uniaxially constrained cell-populated collagen gels with different collagen densities, subjected to immediate or delayed uniaxial cyclic strain with varying strain amplitudes. The simulation outcomes are in agreement with previous experimental reports. Taken together, our computational approach is a promising tool to understand and predict the remodeling of collagenous tissues, such as native or tissue-engineered arteries and heart valves.
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