A CMOS Medium Density DNA Microarray with Electronic Readout
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A CMOS Medium Density DNA Microarray with Electronic Readout Roland Thewes, Christian Paulus, Meinrad Schienle, Franz Hofmann, Alexander Frey, Petra Schindler-Bauer, Melanie Atzesberger, Birgit Holzapfl, Thomas Haneder, and Hans-Christian Hanke Infineon Technologies AG, Corporate Research, D 81730 Munich, Germany ABSTRACT A CMOS chip-based approach is reviewed for fully electronic DNA detection. The electrochemical sensor principle used, CMOS integration of the required transducer materials, chip architecture and circuit design issues are discussed, respectively. Electrochemical and biological results obtained on the basis of medium density microarray sensor CMOS chips with 16 × 8 sensor sites prove proper operation. INTRODUCTION In a wide-spread area of biotech and medical applications tools are required for the parallel detection of specific DNA sequences in a given sample. Most prominent applications are genome research and drug development, while applications in the area of medical diagnosis are under development. Depending on the particular investigation, requirements range from simple "presence or absence" tests to quantitative analyses with a relatively high dynamic range and sensitivity. So-called DNA microarrays [1-6], glass-, polymer, or silicon-based slides with an active area in the order of square millimeters to square centimeters, fulfill this request: There, different species of single-stranded DNA receptor molecules (probe molecules) are immobilized at predefined positions on the chip surface. To investigate a sample, the chip is flooded with the sample containing the target molecules. Complementary sequences of probe and target molecules hybridize, mismatching probe and target molecule do not bind. Finally, after a washing step, double-stranded DNA is obtained at the match positions, and single-stranded DNA (i.e. the probe molecules) remain at the mismatch sites. The information whether double- or single-stranded DNA is found at a given test site reveals the composition of the sample, since the probes and their positions on the chip are known. Consequently, sites with double-stranded DNA or the amount of double-stranded DNA at the different sites, respectively, must be identified. Commercially available state-of-the art DNA microarray chip systems use optical detection techniques for that purpose [1-6]. By avoiding the relatively expensive and complicated optical set-ups required there, electronic readout techniques in principle allow more robust and easier operation. However, so far their status of development is lower. Electronic approaches aiming for low density investigations (i.e. for applications with a low number of sensors sites, e.g. of order 10), usually use a suitable bio-compatible chip substrate material carrying the electrical transducer. The electrical terminals of each on-chip sensor are directly connected to an off-chip reader system. Such "passive chips" represent a cost-effective solution as long as only few sites per investigation are required. In case higher numbers of t
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