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.