ORCID Identifier(s)

0000-0002-7871-3436

Graduation Semester and Year

2020

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Biomedical Engineering

Department

Bioengineering

First Advisor

Michael Cho

Abstract

Islet transplantation is a surgical procedure aimed at providing insulin independence to those suffering with Type I diabetes. Prior to implantation, a therapeutic window exists ex vivo where the cells can be treated in order to improve the procedure’s efficacy. It is well established that physical stimuli are able to affect cellular functionality. Thus the work herein is designed to elucidate the effects and mechanisms by which the insulin secreting β-cells respond to non-invasive electric field stimulation and photobiomodulation. Insulin secreting β-cells are an electrically active cell type and utilize their calcium dynamics to control insulin secretion. The calcium dynamics is driven by the metabolic state of the cell, and thus are stimulated under an elevated glucose environment. Electric field stimulation has been shown to modulate the calcium dynamics in various cell types, but its effects on β-cells has not been fully explored. By adjusting the field strength, membrane depolarization events can be altered, yielding control over the cell’s calcium dynamics and thereby its insulin secretion. Through this control of calcium dynamics, various cellular signaling pathways could be affected for therapeutic benefit. Given the important role the metabolic state plays in the functionality of these cells, near-infrared photobiomodulation could prove an effective therapeutic modality. Similar to electric field stimulation, this modality of external physical stimulation to modulate the β-cell phenotype is its early stage of development. The primary coupling mechanism by which photobiomodulation exerts its effects is through the stimulation of cytochrome c oxidase that leads to an increase in cellular respiration. Given its ability to stimulate the metabolic state of a cell, photobiomodulation could also be used to augment the calcium and insulin dynamics of insulin secreting cells. To further understand the effects of these modalities, we have integrated and modified previously published models to predict the functional effects of these stimuli on β-cells. In so doing, various mechanisms of action could be tested and compared to experimental results. In addition, any synergistic or additive effects could be predicted, thus providing a means of estimating optimal stimulation parameters. By elucidating these mechanisms and cellular responses, this research may open new therapeutic avenues to treating diabetes alongside a better understanding of how β-cells respond to their physical environment.

Keywords

Electric field stimulation, Photobiomodulation, Beta cell physiology, Calcium dynamics, Islet transplantation.

Disciplines

Biomedical Engineering and Bioengineering | Engineering

Comments

Degree granted by The University of Texas at Arlington

Download

Share

COinS