Abstract
Following FDA approval, TTFields treatment has become a commonly used modality for treating patients with Glioblastoma (GBM) and Mesothelioma. From the early 2000’s, extensive research has been performed in in-vitro systems for studying the effects of TTFields on living cells. These studies have shown that multiple cellular functions are affected by TTFields. However, the physical mechanism by which the fields exert effects on cells are not well understood. We propose an analytical model for predicting the geometric and electrical parameters enabling amplification of the electric field in the living cells. This amplification favors the emergence of local heating, dielectrophoretic (DEP) force, or electrostatic pressure at TTFields frequencies. This model is supported by simulations of cells in different configurations. Computational studies were performed with Comsol Multiphysics software. Cell models were constituted of cytoplasm, membrane and extracellular matrix. A field of 1V/cm was generated at different frequencies between 10kHz and 1GHz. Maximal field amplification of X20 of the applied field (@200 kHz) was observed in a model of confluent cells with 5nm intercellular distance. Such field amplification could create electrostatic pressure on the membrane potentially leading to its deformation and to stress on the cytoskeleton. Analytical calculations show the field gradient could result in DEP forces of ~10pN on the membrane. Such force could potentially disrupt the membrane or junctions. Results show that a 10nm pore in membrane would lead to a 450 times amplification in the pore’s vicinity, potentially resulting in forces of between 0.1pN and 100pN on intracellular structures. Those forces are sufficient for disrupting microtubules. Specific Absorption Rates of up to 106 W/kg were observed in the vicinity of the pore, suggesting that strong thermal effects may also explain the effect of TTFields on cells. Our generic analytical model predicts the conditions for field amplification at TTFields frequencies.