The processes in which cardiac cells are reorganized for tissue regeneration is still unclear. It is a complicated process that is orchestrated by many factors such as mechanical, chemical, thermal, and/or electrical cues. Studying and optimizing these conditions in-vitro is complicated and time costly. In such cases, in-silico numerical simulations can offer a reliable solution to predict and optimize the considered conditions for the cell culture process. For this aim, a 3D novel and enhanced numerical model has been developed to study the effect of the mechanical properties of the extracellular matrix (ECM) as well as the applied external forces in the process of the cell differentiation and proliferation for cardiac muscle tissue regeneration. The model has into account the essential cellular processes such as migration, cell-cell interaction, cell-ECM interaction, differentiation, proliferation and/or apoptosis. It has employed to study the initial stages of cardiac muscle tissue formation within a wide range of ECM stiffness (8-50 kPa). The results show that, after cell culture within a free surface ECM, cells tend to form elongated aggregations in the ECM center. The formation rate, as well as the aggregation morphology, have been found to be a function of the ECM stiffness and the applied external force. Besides, it has been found that the optimum ECM stiffness for cardiovascular tissue regeneration is in the range of 29-39 kPa, combined with the application of a mechanical stimulus equivalent to deformations of 20-25%.

Electrical and mechanical stimulations play a key role in cell biological processes, being essential in processes such as cardiac cell maturation, proliferation, migration, alignment, attachment, and organization of the contractile machinery. However, the mechanisms that trigger these processes are still elusive. The coupling of mechanical and electrical stimuli makes it difficult to abstract conclusions. In this sense, computational models can establish parametric assays with a low economic and time cost to determine the optimal conditions of in-vitro experiments. Here, a computational model has been developed, using the finite element method, to study cardiac cell maturation, proliferation, migration, alignment, and organization in 3D matrices, under mechano-electric stimulation. Different types of electric fields (continuous, pulsating, and alternating) in an intensity range of 50–350 Vm−1, and extracellular matrix with stiffnesses in the range of 10–40 kPa, are studied. In these experiments, the group’s morphology and cell orientation are compared to define the best conditions for cell culture. The obtained results are qualitatively consistent with the bibliography. The electric field orientates the cells and stimulates the formation of elongated groups. Group lengthening is observed when applying higher electric fields in lower stiffness extracellular matrix. Groups with higher aspect ratios can be obtained by electrical stimulation, with better results for alternating electric fields.

Oxygen concentration plays a key role in cell survival and viability. Besides, it has important effects on essential cellular biological processes such as cell migration, differentiation, proliferation and apoptosis. Therefore, the prediction of the cellular response to the alterations of the oxygen concentration can help significantly in the advances of cell culture research. Here, we present a 3D computational mechanotactic model to simulate all the previously mentioned cell processes under different oxygen concentrations. With this model, three cases have been studied. Starting with mesenchymal stem cells within an extracellular matrix with mechanical properties suitable for its differentiation into osteoblasts, and under different oxygen conditions to evaluate their behavior under normoxia, hypoxia and anoxia. The obtained results, which are consistent with the experimental observations, indicate that cells tend to migrate toward zones with higher oxygen concentration where they accelerate their differentiation and proliferation. This technique can be employed to control cell migration toward fracture zones to accelerate the healing process. Besides, as expected, to avoid cell apoptosis under conditions of anoxia and to avoid the inhibition of the differentiation and proliferation processes under conditions of hypoxia, the state of normoxia should be maintained throughout the entire cell-culture process.

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.

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