Sanz Herrera, José AntonioReina Romo, EstherCarrasco Mantis, Ana2025-07-282025-07-282025-05-23Carrasco Mantis, A. (2025). Numerical Models of cell Mechanobiology oriented to organic Vascularization. (Tesis Doctoral Inédita). Universidad de Sevilla, Sevilla.https://hdl.handle.net/11441/175717In the investigation of the role of mechanical cues in biology, i.e., mechanobiology, in silico modeling is used to complement in vivo and in vitro models, guided by the development of computers and algorithms that make it possible to apply engineering tools to living beings. Rather than the ambitious goal of predicting the evolution of a biological system, like a disease, many of them without a therapeutic treatment, in silico modeling tries to identify elements that may be important in the development of such problems and provides tools to measure and quantify magnitudes that would be very difficult to obtain through experiments. In this thesis, 3D in silico models of some important cellular processes in mechanobiology are constructed. To this end, this thesis begins by studying the evolution of spheroids, particularized for a type of brain cancer, Glioblastoma Multiforme (GBM). This approach allows for the replication of key phenomena, such as cellular communication mechanisms, nutrient gradient effects and the formation of realistic 3D biological structures. The primary aim of this research is to connect the evolution of spheroids to the mechanical activity of cells, integrating nutrient diffusion, consumption and the resulting cellular dynamics of growth and death through a 3D continuum mechanobiological model that is qualitatively validated with own experiments. The model offers a novel explanation for diverse scenarios, such as spheroid growth and shrinkage, behavior attributed to the mechanical interactions among cells, guided by their evolutionary dynamics. Subsequently, it is analyzed how the extracellular matrix (ECM) passively stimulates vascularization. Vasculogenesis, the process of forming new blood vessels, is influenced by numerous factors, biochemical and biomechanical. Nevertheless, the biomechanical factors that impact the shape, organization, and structure of vascular networks remain poorly understood and require further study. A 3D agent-based model (ABM) of vasculogenesis is developed to explore how the mechanical properties of the ECM influence this process. To achieve this goal, a growing domain containing different endothelial cell types is modeled: tip cells, that sense the chemotactic gradient and lead the growth at the ends of the vessels, and stalk cells, which form the interior of the vascular network. The ECM is represented as particles surrounding the developing vascular structure. Various forces are incorporated depending on the cell type, including chemotactic, mechanical, random, and viscoelastic forces, among others. The network is analyzed and updated iteratively at each time step using a mechanically-driven proliferation rule. Through in silico simulations, the impact of various biomechanical factors, such as ECM stiffness and viscoelasticity, is investigated. Several indicators, including the number of cells, branches, tortuosity, and anisotropy, are defined throughout the algorithm to assess topological variations in the vascular network during vasculogenesis under different ECM conditions. The results are qualitatively compared with findings from other related studies in the literature. Finally, a hybrid model is developed, combining both continuum and discrete formulations, to simulate the vascularization process in an organoid, a model similar to the spheroid but with a more complex structure, in an attempt to study in silico the lack of vascularization that limits the usefulness of this type of in vitro models. Organoids replicate hierarchical functions, acting as miniature versions of living tissues and providing a reliable representation of cellular mechanisms. The model combines a finite element and agent-based frameworks to incorporate the mechanical stimulation through a laminar and stationary flow and the main biophysics within the organoid. It analyzes parameters such as fluid velocity and nutrient consumption along the organoid evolution, whose results agree qualitatively.application/pdf202 p.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/openAccess