The Role of Extracellular Environment in Regulation of Cellular Response to Electric Field

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Chronic wounds impose a significant burden on patients and health care system because they do not effectively respond to pharmacological treatments. Developing new non-pharmacological treatments requires application of advanced technology to control natural cell signals to trigger the desired cell responses. Electric field (EF) generated in the ionic environment surrounding cells and cell membrane has been shown to control cell behaviors. Therefore, manipulation of this EF by external EF may provide a new non-chemical treatment. EF-cell interactions may be affected by both the distribution of the induced EF within the cell and the properties of the extracellular matrix (ECM), which is known to regulate cell response to the external stimuli. Therefore, mechanistic studies of cell-ECM interaction in response to EF are essential for the efficient control of cell responses and development of EF-based therapies. To address this issue, we developed a combined theoretical-experimental approach. Theoretical 3D EF-cell interaction model solves Maxwell's equations (ANSOFT_HFSS) for a membrane-enclosed hemisphere subjected to EF in its native configuration to provide a precise distribution of induced EF within the cell in wide frequency range. Simulation results predict a frequency specific cell response. At low frequency EF is confined in cell membrane and expected to regulate membrane-initiated responses. At high frequency EF penetration into the cell increases and is therefore expected to activate intracellular interactions. Experimentally measured responses of endothelial cells to EF confirm this prediction. Analysis of growth factor expression and capillary morphogenesis show a significant difference between low and high frequency groups. Blocking membrane receptors does not affect observed responses in high frequency, which confirms activation of intracellular interaction. We showed that cell responses to EF function differently in natural versus synthetic ECM. We attribute this to difference in ECM properties.