1. Introduction
Glioblastoma multiforme (GBM) is the most aggressive and invasive human brain cancer of glial cells1-3. It has massive intratumor and intertumoral heterogeneity due to its highly complex and dynamic microenvironment. There is a bidirectional interaction in GBM in which tumor microenvironment shapes cellular state of glioma cells and a glioma cell with inherited plasticity expands tumor heterogeneity4. Understanding the characteristic features of glioma cells emerges as an important path to reveal heterogeneity of tumor microenvironment to provide novel therapeutic approaches that successfully targets molecular and morphological alterations in the subsets of GBM, and eventually increase treatment efficacy5-8.
Glioma cells display striking cellular heterogeneity by changing their morphology9-11, nuclear volume12-14, cell-cell adhesion15,16, cellular interactions17, remodeling their cytoskeleton organization18-21, performing epithelial to mesenchymal (EMT)22-24, glioma-associated stem (GASC)24,25 or glioma-initiating stem cell (GISC) transitions24,26. We need adequate tools to characterize these dynamic variations of glioma cells in the tumor microenvironment without altering genetic and phenotypic properties of the cells10. Precisely quantifying these features of glioma cells might identify indicators to reveal their invasive behavior10. Hence, we can develop accurate and precise treatment strategies that targets right subpopulations of glioma cells.
Recent studies have demonstrated effective tools to investigate mechanical27, adhesive, and invasive features of glioma cells using fluorescence microscopy15-27, 2-photon imaging11,28, atomic force microscopy16,29,30, single-cell force spectroscopy16, microfluidic chips31-39. Dielectrophoretic methods to investigate electrical properties of glioma cells have not been completely developed, in contrast to mechanical techniques. In this context, Balck and co-workers reported the immunological, biochemical, ultrastructural, and electrophysiological characteristics of a human glioblastoma-derived cell culture line in 198240, since then, revealing dielectric properties of glioma cells have been recently accelerated. Pohl established the dielectrophorsis (DEP) phenomenon in the 1950s. He reported that dielectric properties of a cell (particle) can be elucidated by introducing them into non-uniform eclectic field that exerted dielectrophoretic forces on a cell as a function of frequency42. When DEP forces can be rapidly and accurately measured, some intrinsic cellular parameters can be acquired such as crossover frequency. Notably, it has been shown that DEP forces are one of the gentlest forces which do not cause genetic or phenotypic variations43. Although several cancer-cell lines have been dielectrophoretically characterized using electrode arrays embedded in the microfluidic channels44-48, still characterization of glioma cells is very limited 48.
In this work, we have investigated the dielectric properties of glioma cells using an array of planar electrodes in a microfluidic channel. We presented distribution of the electric field gradient in the device using COMSOL simulation. We monitored dielectrophoretic behavior of glioma U87 cells and determined their dielectrophoretic response by precisely measuring positions of the 500 single glioma cells.