Multiparametric silicon sensor chips mounted into biocompatible cell culture units have been used for investigations on cellular microphysiological patterns. Potentiometric, amperometric and impedimetric microsensors are combined on a common cell culture surface on the chip with an area of approximately 29 mm2. Extracellular acidification rates (with pH-sensitive field effect transistors, ISFETs), cellular oxygen consumption rates (with amperometric electrode structures) and cell morphological alterations (with impedimetric electrode structures, IDES) are monitored on single chips simultaneously for up to several days. The corresponding test device accommodates six of such sensor chips in parallel, provides electronic circuitry and maintains the required cell culture conditions (temperature, fluid perfusion system). Sensor data are transformed into quantitative information about microphysiologic conditions. The outcome of this transformation as well as reliability and sensitivity in detection of drug effects is discussed. This is the first report on multiparametric cell based assays with data obtained solely with integrated sensors on silicon chips. Those assays are required in different fields of application such as pharmaceutical drug screening, tumor chemosensitivity tests and environmental monitoring.
The identification of drug targets for pharmaceutical screening can be greatly accelerated by gene databases and expression studies. The identification of leading compounds from growing libraries is realized by high throughput screening platforms. Subsequently, for optimization and validation of identified leading compounds studies of their functionality have to be carried out, and just these functionality tests are a limiting factor. A rigorous preselection of identified compounds by in vitro cellular screening is necessary prior to using the drug candidates for the further time consuming and expensive stage, e.g. in animal models. Our efforts are focused to the parallel development, adaptation and integration of different microelectronic sensors into miniaturized biochips for a multiparametric, functional on-line analysis of living cells in physiologically environments. Parallel and on-line acquisition of data related to different cellular targets is required for advanced stages of drug screening and for economizing animal tests.
The lateral oxidation of buried Al x Ga 1Ϫx As layers with high Al content (xϭ0.8-1) is investigated, using an oxidation process in a wet N 2 ϩH 2 O ambient at 370-450°C. The oxidation is clearly selective and significantly affected by process temperature, material composition, Al x Ga 1Ϫx As layer thickness, and the geometry of the oxidized structures. An asymptotic oxide growth with constant activation energies for the reactive process and for the transport mechanism is observed. The experimental oxidation behavior coincides well with a model of self-blocking pores.
Impedance sensors in thick film technology have been tested as a tool for electric cell-substrate impedance sensing. The screen printed Pt electrodes have a width of 250-400 microm. Electrodes and the surrounding ceramic chip substrate could be homogeneously grown with L-929 and Hela cells. The performance of a screen printed interdigitated electrode structure (IDES) was compared with that of thin film structures with the same layout geometry. The thick film impedance sensors allowed to correctly record the morphological response of confluent Hela cell layers to stimulation with histamine. A thick film conductivity sensor also revealed impedance values which were dependent on cell growth on the electrode surface, even at a very low frequency range of approximately 1 Hz.
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