Development of effective treatments for impaired healing of vascular tissues is essential to address significant health care problems associated with these conditions, including chronic ulcers. Clinical studies reveal that an electric field has the potential as a novel vascular therapy to accelerate healing of hard-to-heal wounds. However, widespread acceptance of electric field therapies for wound healing has been prevented by a lack of standardized protocols, leading to variabilities in healing outcomes. External electric fields can affect a variety of vascular cell responses through the manipulation of the native electric field in the extracellular ionic environment and across the cell membrane. Therefore, an electric field, together with the extracellular matrix and a milieu of cytokines, represents a biophysical system that ultimately regulates vascular cell function. Therapeutic modulation of this system requires advanced integration of knowledge and technology from both physics and biomedical sciences. The long term goal of this research is to create non-pharmacological, electric field-based therapies for non- or slow-healing chronic ulcers. The studies in this research contribute to this goal by developing a theoretical-experimental approach to elucidate the biophysical mechanisms of cell- electric field interactions mediated by the extracellular matrix.

The numerical model of cell-electric field interaction determines the distribution of the induced electric field in the cell and extracellular environment. The novelty of the model is that it considers the cell attached to a substrate to represent cells within tissues. The results show a striking difference in the (1) frequency dependence of electric field penetration and (2) cell response between cells suspended in an electrolyte and cells attached to a substrate. The results demonstrate that, at low frequency, electric field is confined in the cell membrane and is expected to regulate membrane-initiated responses. At high frequency, electric field penetrates the cell and may directly activate intracellular responses .Importantly, the sensitive dependence of electric field distribution in the cell to the physical properties of the cell and its environment is demonstrated. Additionally, the advantage of non- contact electric field application for research and therapeutic purposes is discussed.

The experimental studies of cell– electric field interaction confirm the theoretical predictions and show the frequency- specific cell responses and demonstrate the intracellular pathway activation in response to high frequency electric field when electric field is induced in the intracellular space. The results show that extracellular matrices with different matrix properties can differentially regulate protein expression in response to the high frequency electric field, confirming the importance of incorporating substrate properties to study cell-field interactions. Importantly, cell responses that promote wound healing process are activated following electrical stimulation.

Further, this study provides novel information about interaction of cells with surface charges generated in DC regime. Finally, the deficiencies of endothelial cells in diabetic condition are determined and the effect of electric field in improving the diabetic endothelial cell response is demonstrated.

These findings improve the mechanistic understanding of vascular cell interactions within the complex biophysical system and can potentially contribute to development of electric field-based therapies for vascular tissue regeneration.