Ivar Giaever

A Biosensor using Living Cells


Abstract

Introduction

Deciphering the fundamental differences in the behavior of normal and cancer cells is of paramount importance in understanding and eventually curing cancer. It is difficult to measure cell behavior within whole organism, therefore many scientists study cells grown outside of the body in tissue culture. Cells in tissue culture carry on much of their normal activities including cell division. The differences in the behavior of normal and cancer cells in tissue culture are generally studied by making microscopic observations sometimes coupled with time-lapse video-equipment and image processing. We have developed a new electrical impedance method to examine cells in vitro that we refer to as Electric Cell-substrate Impedance Sensing or ECIS. This method augments very nicely the optical microscope and can reveal many new aspects of cell behavior. Furthermore, the approach is highly sensitive to morphological changes in the shape and presents quantitative data in real time.

Description of ECIS

In this method cells are cultured on small gold electrodes using standard culture medium as the electrolyte and placed in an ordinary incubator designed for cell growth. By applying a small alternating current to the electrodes, we can measure the electrical impedance of the electrodes from outside the incubator, and it is unnecessary to remove the cells to examine them. As cells anchor and spread on the active electrodes, their insulating plasma membranes constrain the electrical current and force it to flow beneath and between the cells. This convoluted current path causes large changes in the measured impedance. In addition, small fluctuations in the impedance are observed because the live cells continuously alter their morphology or shape. Through these tissue culture studies we aim to better measure and understand the mechanisms involved in cancer and other illnesses.

Metastatic behavior revealed in tissue culture

We have used ECIS to study metastasis in vitro using a modification of microscopic studies of the process introduced by G. Nicholson. In this work, a monolayer of the cells making up the capillaries (endothelial cells) was first established. This layer was then exposed to a suspension of cells with different metastatic abilities. For highly metastatic melanoma cell lines, one observed first the binding of the cells and next the penetration of the cancer cells through the endothelial monolayer. This type of assay provides striking microscopic images of the behavior of the metastatic cell but by nature is difficult to quantify and cannot provide information in real time regarding the dynamics of the process.

Application of ECIS to metastesis

ECIS furnishes a new means to quantify this behavior. In this work a layer of human endothelial cells was challenged with the rat prostatic cancer cell lines having varying metastatic abilities in vivo. ECIS data clearly detects the metastatic behavior of the cancer cells and can also differentiate between the metastatic abilities of the different lines. We hope that in time this research may find clinical application in evaluating breast, prostatic and other tumors.


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