Enhanced Piezoelectric Fibered Extracellular Matrix to Promote Cardiomyocyte Maturation and Tissue Formation: A 3D Computational Model

SIMPLE SUMMARY: Cell development for tissue regeneration depends on the mechanical and the electrical stimuli present in the cell microenvironment. This is especially relevant for tissues with complex cellular structures such as cardiac tissue. To recognize the complex interaction of the cell with its microenvironment, it is necessary to understand the role of the mechanical forces generated by the previously mentioned stimuli in the cell behavior. Studying this process, through in vitro models, requires a large number of experiments, with a high economic and time cost. In this sense, computational methods are capable of reproducing cell mechanics within complex microenvironments considering cell–cell and cell–extracellular matrix interactions. Thus, we have developed a 3D computational model to reproduce this process. With this model, different experiments have been purposed to study cardiac cell differentiation and aggregate morphology, under different extracellular matrix configurations. According to the results, group morphologies are determined by the intensity and the directionality of the applied stimuli. Using the developed model, it is possible to develop parametric studies to determine the suitable preliminary conditions for adequate tissue development, reducing the number of in-vitro experiments. ABSTRACT: Mechanical and electrical stimuli play a key role in tissue formation, guiding cell processes such as cell migration, differentiation, maturation, and apoptosis. Monitoring and controlling these stimuli on in vitro experiments is not straightforward due to the coupling of these different stimuli. In addition, active and reciprocal cell–cell and cell–extracellular matrix interactions are essential to be considered during formation of complex tissue such as myocardial tissue. In this sense, computational models can offer new perspectives and key information on the cell microenvironment. Thus, we present a new computational 3D model, based on the Finite Element Method, where a complex extracellular matrix with piezoelectric properties interacts with cardiac muscle cells during the first steps of tissue formation. This model includes collective behavior and cell processes such as cell migration, maturation, differentiation, proliferation, and apoptosis. The model has employed to study the initial stages of in vitro cardiac aggregate formation, considering cell–cell junctions, under different extracellular matrix configurations. Three different cases have been purposed to evaluate cell behavior in fibered, mechanically stimulated fibered, and mechanically stimulated piezoelectric fibered extra-cellular matrix. In this last case, the cells are guided by the coupling of mechanical and electrical stimuli. Accordingly, the obtained results show the formation of more elongated groups and enhancement in cell proliferation.