Synergy of Microchip Technology and Living Cells

During the past few years, microsystems technology or microelectronics - and especially chip fabrication techniques - have been utilized to design and produce new types of microchips that can be employed in medicine to control heart pacemakers, drug delivery microimplant systems, or as replacements for neural tissues (e.g., retinal implants and brain pacemakers). As rational screening tools for drug discovery and development, as well as for clinical diagnosis, microarrays are applied to the investigation of nucleic acids, proteins, bacteria, viruses, cells, and tissues. In particular, cell- and tissue-based microchips (biochips) are attracting increasing attention as they can provide information not only about the simple binding and activity of promising drug candidates, but also about their effect on the physiology of biological systems. In order to obtain these functional data, it is necessary to bring cells or tissues into close contact with substrate (silicon, glass or polymers) -embedded microelectrodes. Here, drug-induced alterations in the extracellular potential, which are usually generated by local ion fluxes over the cell membranes, are measured electronically against a stable reference electrode, whereby the microelectric readout can be carried out simultaneously online and in real-time on multiple microlelectrodes. Although these recordings using multielectrode arrays (MEAs) or multi-microelectrode arrays (MMEAs) represent a powerful technique to measure electrophysiological alterations of excitable single cells or even tissues [1-9], cells without any electric activity cannot be analyzed. An alternative method for the measurement of intrinsic and extrinsic cellular properties of both electrophysiologically active and inactive cells is provided by bioimpedance spectroscopy [10-14]. In principle, a similar multielectrode array configuration (as described above for electrically active cells) can be used for impedance spectroscopy, by which the impedance ofintracellular and extracellular compartments is measured simultaneously at different frequencies on multiple electrodes. A further chip-based in-vitro screening system for analyzing the physiological state of cells is that of multiparametric chips [15, 16]. This type of biochip or biosensor is characterized by the implementation of different types of electrodes in one device. Cellular parameters such as metabolism, mitochondrial activity, and cytoskeletal integrity can be measured, for example, with ion-sensitive field effect transistors (ISFET, for measuring pH changes), interdigital electrode structures (IDES, for monitoring membrane properties), and amperometric electrodes (for measurements of glucose and oxygen consumption).

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