Document Type

Dissertation

Date of Award

Fall 12-31-2018

Degree Name

Doctor of Philosophy in Chemical Engineering - (Ph.D.)

Department

Chemical and Materials Engineering

First Advisor

Roman S. Voronov

Second Advisor

Edward L. Dreyzin

Third Advisor

Treena Livingston Arinzeh

Fourth Advisor

S. Basuray

Fifth Advisor

Murat Guvendiren

Abstract

Cell migration in complex micro-environments, that are similar to tissue pores, is important for predicting locations of tissue nucleation and optimizing scaffold architectures. Firstly, how fibroblast cells - relevant to tissue engineering, affect each other’s directional decisions when encountered with a bifurcation of different channel lengths was investigated. It was found that cell sequence and cell mitosis influence the directional choices that the cells made while chemotaxing. Specifically, the fibroblasts chose to alternate between two possible paths - one longer and the other shorter - at a bifurcation. This finding was counter-intuitive given that the shorter path had a steeper chemoattractant gradient, and would thus be expected to be the preferred path, according to classical chemotaxis theory. Hence, a multiscale image-based modeling was performed in order to explain this behavior. It showed that consumption of the chemotactic signals by the neighboring cells led to the sequence-dependent directional decisions. Furthermore, it was also found that cellular division led to daughter cells making opposite directional choices from each other; even it meant that one of the daughter cells had to move against the chemotactic gradient, and overcome oncoming traffic of other cells.

Secondly, a comparison of the effects of the various directional cues on the migration of individual fibroblast cells: including the chemoattractant concentration gradient, the channel width, and the contact-guidance was provided. Simple bifurcated mazes with two branches of different widths were created and fibroblasts were allowed to travel across these geometries by introducing a gradient of PDGF-BB at the ‘exit’ of the device. By incorporating image-based modeling methodology into the experimental approach, an insight into (i) how individual cells make directional decisions in the presence of complex migration cues and (ii) how the cell-cell interaction influences it was provided. It was found that a larger width ratio between the two bifurcated branches outdoes a gradient difference in attracting the cells. Also, when cells encounter a symmetric bifurcation (i.e., no difference between the branch widths), the gradient is predominant in deciding which path the cell will take. Then, in a symmetrical gradient field (i.e., inside a bifurcation of similar branch widths, and in the absence of any leading cells), the contact guidance is important for guiding the cells in making directional choices. Finally, these directional cues were ranked according to the order from the most importance to the least: vast gradient difference between the two branches, channel width bias, mild gradient difference, and contact-guidance.

Share

COinS