Bio-electronic transducers to interact with cancer cells

• Autor(a) principal: Brázio, Diogo Luzia
• Data de Publicação: 2020
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.1/15153
• topic: Intercellular; Messengers incurable; Brain; In homeostasis; Glioma cells; Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias

This thesis is focused on the study of electrophysiological signals in populations of cancer cells measured using extracellular electrodes. The cells under study are derived from cells known as glia cells. Glia cells are part of the brain but are significantly different from neurons. An important function of glia cells is to regulate communication between neurons. Glia cells can mutate and turn into cancer cells. When this happens, they give rise to very aggressive tumors (gliomas). The study of electrophysiological signals in cells of this type is relevant because in principle it can give information about how this type of cells is organized and communicates to perform simple tasks, such as migrating or proliferating. In contrast to neurons, or cardiomyocytes, glia cells do not generate action potentials and therefore, are included in the class of non-electrogenic cells. However, glia cells have developed an information transmission mechanism that is based on the generation of a local ionic oscillation. This oscillation can travel to neighboring cells like a wave. To generate the oscillation, the cells generate a flow of ions, for example of calcium or sodium ions, the associated electrical oscillations are known as calcium or sodium waves, respectively. Ionic oscillations can travel long distances (millimeters). For the oscillation to travel through the cell population, cells must be connected to form a compact biological tissue. The formation of the wave also requires that the cells have the ability to synchronize their activity. Unlike an action potential, that is an oscillation generated by an individual cell, the oscillations generated by glia cells are a property of a set of cells that synchronize to generate electrical fluctuation. Note that both the action potential and the wave generated by the glia cells are both electrical signals that travel like waves. However, there are important differences in the characteristics of the two signals. An action potential is a fast signal (meters / s) and short duration (milliseconds). A calcium wave is an oscillation that can last for several seconds and propagates through the population of cells at speeds of a few tens of micrometers per second. A calcium wave is typically a thousand times slower than an action potential. The measurement and interpretation of action potentials using extracellular electrodes is well documented in the literature. As for the electrical waves generated by the synchronized activity of cells, the knowledge is very poor. Until now, this type of bio-electrical signaling mechanism has been studied using optical markers and fluorescence techniques. Although, optical techniques can visualize the wave, they suffer from a set of limitations, both from experimental as well as from a biological point of view. For example, optical markers have a relatively short lifetime (hours), and can be toxic to cells. Additionally, light can disturb the measurements. Optical florescence has in its favor the fact that it is a selective technique and allows to know exactly the ionic species that is involved in the process. Electrical techniques cannot differentiate which ion is involved, but they can observe oscillations in real time in a totally noninvasive way and for extended periods (weeks or months). The existing literature on the signal analysis and processing of signals that are result from synchronized cell activity is practically non-existent. This scientific area is still in its infancy. This thesis aims to contribute to increase our knowledge about this type of bio-electric signaling. The objective of the work presented in this thesis was to study how the design of extracellular electrodes determines the shape of the measured electrical signal. Since the signal is an electric wave that travels through the cell population, it is obvious that the shape of the signal is essentially determined by a number of factors, namely the; (i) number of cells that are able to synchronize, (ii) electrode design, (iii) electrode active area, and even (iv) spatial arrangement of the electrodes in relation to the wave propagation direction. This study processed a large number of signals collected using electrodes with different areas and geometries. The signals were first cataloged and classified according to the shape of the measured signal. Then, relationships were established between the power of the measured signal and the active area of the measured electrode, the periodicity of the signal and the spacing of the sensor electrodes. The components of the signal that vary exponentially have been quantified to determine the physical origin of the exponential behavior, or in other words if it originates in a biological process or if it is determined by the time constant (physics) of the electrode. Finally, several signal patterns were characterized and classified. Among the most interesting patterns, a pattern in which the frequency increases following an exponential law (called a blueshift) and a pattern where the frequency decays exponentially (redshift) were observed. The results of the signal analysis and their relationship with the geometry of the electrodes allowed us to quantify the role of the electrode in defining the shape and the duration of the signal. Guidelines for the optimization of the electrodes was also an important outcome of this thesis. Finally, it is important to note that from the biological point of view it is expected that the optimization of the electrodes will allow to decode signaling patterns that correspond to specific biological instructions. For example, assuming that cell migration is a process instructed by an electrical oscillation with a certain pattern, decoding this pattern will eventually enable us to inhibit cell migration, thus paving the way for new technologies for cancer therapy. The limitations of using radiotherapy and chemotherapy in the brain make electrical techniques particularly appealing to treat brain tumors.