Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Physics

Supervisor

Karttunen, Mikko

Abstract

The growth of biological matter, e.g., tumor invasion, depends on various factors, mainly the tissue’s mechanical properties, implying elasticity, stiffness, or apparent viscosity. These properties are impacted by the characteristics of the tissue’s extracellular matrix and constituent cells, including, but not limited to, cell membrane stiffness, cell cytoskeleton mechanical properties, and the intensity and distribution of focal adhesions over the cell membrane. To compute and study the mechanical properties of tissues during growth and confluency, a theoretical and computational framework, called CellSim3D, was developed in our group based on a three-dimensional kinetic division model.

In this work, CellSim3D is updated with a new set of cell mechanical parameters and force fields such as the asymmetric division rule, shape diversity, apoptosis process, and boundary conditions, e.g., periodic and Lees-Edwards boundary conditions. The package is upgraded to operate on multiple GPUs to further accelerate computations. This enables the inclusion of more complexity in the system. For instance, the simulation of macroscopic scale bicellular tissue growth with precise control over the mechanical properties of cells is now more feasible than before.

The effects of cell-cell adhesion strength and intermembrane friction on growth kinetics and interface roughness dynamics of epithelial tissue were studied. It is reported that with fine alterations of the mechanical parameters such as the cell-cell adhesion strength, one could reliably reproduce different interface roughness scaling behaviors such as Kardar–Parisi–Zhang (KPZ)-like and Molecular Beam Epitaxy (MBE)-like scaling. In addition, it was observed that substrate heterogeneity and geometry have significant impacts on the morphology and interface roughness scaling of epithelial tissue. The results suggest that the interface roughness scaling of epithelial tissues cannot be classified by any well-known scaling universality class. Instead, it strongly depends on several other factors, such as the cell-cell adhesion strength. This explains the controversies observed in earlier experimental works over the interface roughness scaling of expanding epithelial tissue.

Summary for Lay Audience

The development and progression of human diseases such as asthma and cancer depend on various factors, including the mechanical properties of the tissue or tumor. These mechanical properties are dependent on the mechanical properties of the cells that comprise the tissue and tissue substrate. Due to rapid advances in experimental techniques and computational capacity, the scientific community has made progress in modeling tissue growth and dynamics over the past few decades. CellSim3D is a theoretical and computational framework that models cells in three-dimensions with functional mechanical properties such as cell membrane stiffness and cell-cell adhesion in order to study tissue growth and dynamics. We upgraded CellSim3D to simulate tissue growth with new features such as cell shape diversity, the cell apoptosis process, and bicellular tissue growth. The current version of the software has also been upgraded to simulate tissue growth and dynamics with millions of cells. We used CellSim3D to study the impact of cell mechanical properties on tissue interface roughness. We showed that cell mechanical properties, such as cell-cell adhesion strength, have a substantial effect on the colonies' interface roughness, from a jagged to a smooth interface. In addition, we also demonstrated the extent to which substrate geometry and heterogeneity influence the interface roughness and morphology of cell tissues. These findings emphasize the important impact of parameters such as cell mechanical properties and substrate heterogeneity on the roughness of tissue interfaces, which also explains the differing interface roughness observed in the tissue growth experiments. Studying the interface roughness of biological substances can aid in disease diagnosis and prognosis. For example, tumors with a coarser surface are frequently more aggressive and susceptible to metastasis.

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