Electrical pulse induced biological effects using dielectric spectroscopy and mathematical models.

Abstract

This dissertation studies the effects of pulsed electric fields (PEFs) on biological cells by measuring the changes in the electrical properties of the pulsed cells and mathematically modeling avascular tumor growth, cell population dynamics, and Ohmic heating. These issues are critical because of the recent use of intense ultrashort PEFs for various biological and medical applications. Recent research using PEFs for tumor treatment motivated an investigation of a simple model for the growth of an avascular tumor. We modeled tumor growth before and after necrotic core formation by incorporating spatial dependence into a one dimensional scaling law. This model emphasized the importance of cell metabolic rate in determining the final steady state size of the tumor. Experimental results showing changes in cell survival and cell cycle due to PEFs led to an investigation of a simple mathematical model for cell population dynamics that considered the cells to be proliferating (dividing) or quiescent (resting). Although some cell populations apparently reached steady state quickly, the proliferating cell population fell below one, meaning that the overall cell population would eventually decay away. This result, which was unaltered by including a transition from the quiescent to proliferating state, emphasized the importance of targeting proliferating cells for successful cancer treatments. Time domain dielectric spectroscopy was used to measure the electrical properties of a biological cell suspension over a wide frequency range with a single pulse following multiple PEFs. Fitting the dielectric properties of a cancer cell (Jurkat) suspension to a double shell model yielded the dielectric parameters of the cell membrane, cytoplasm, nuclear envelope, and nucleoplasm. Decreased cytoplasm and nucleoplasm conductivity and increased suspension conductivity suggestion transport from the cell interior to the exterior consistent with electroporation. Reduced cell membrane conductivity suggests possible changes in ion channel structure or function. PEF-induced heating is a concern because of the desire to distinguish between electrical and thermal effects. A model for cellular Ohmic heating showed that a typical ultrawideband electrochemotherapy pulse heated the cell by 0.05 C. The heat dissipated rapidly, indicating that Ohmic heating from multiple pulses is not cumulative.