Electronic Detection of DNA Hybridization: Toward CMOS Microarrays Luca Benini University of Bologna Carlotta Guiducci ESPCI-Paris Christian Paulus Siemens AG &THE HEREDITARY CHARACTERISTICS of human beings and of most living organisms are stored in DNA double-helical molecules folded into complex suprastructures and confined in cell nuclei. DNA code consists of long sequences (strings) of four building blocks, called bases or nucleotides. DNA analysis can explain differences between species, distinguish between different individuals, and identify variations in gene expressions caused by diseases and their treatments. Discovery and systematization of this huge amount of information relies heavily on high-through- put analysis devices. Such devices can test a sample for the many DNA sequences that relate to several different genes by comparing the sample with known sample sequences called probes. In the past decade, miniaturized gene-based test arrays known as comple- mentary-DNA (cDNA) microarrays and oligomicroar- rays have matured as commercial products. Some of these devices, implemented with photo- lithographic techniques, can test an entire genome, with densities of a million sites per square centimeter. 1 These devices employ optical detection principles. The sample’s DNA strands are marked with fluorescent molecular labels, and the sample is deposited on the array. Then, a highly specific hybridiza- tion reaction occurs, in which the probes match the sample sequence. The sample is then washed away, but sample sequences remain attached to the matching probes, and an optical scanner or a fluorescence microscope can detect these sequences on specific sites. However, the optical scanner’s high cost, the cost and unreliability of optical labels, and the complex data-processing procedures for extracting useful in- formation from these arrays limit the practicality of these techniques. 2 For this reason, there is consider- able research devoted to developing microarray platforms suitable for low-cost mass production. These devices could target huge markets and bring enor- mous benefits in fields such as disease diagnosis, biothreat detection, and food and drug safety. Arrays capable of direct electronic detection of probe-sample interactions could achieve significant cost reduction and better system integration. Label- free operations would provide additional benefits. Label-free sensors directly detect the interaction between probes and the sample without requiring optically or electrically active molecules attached to the sample. In the past few years, researchers have proposed several labeled and label-free sensor proto- types featuring direct electronic detection. Here, we focus mainly on fully electronic microarrays, with single-chip implementations in CMOS technology. Although biochemical operations in CMOS-based arrays are almost the same as in optical devices, the Editor’s note: Low-cost mass fabrication methods and label-free biosensors are needed for many applications. This article presents a CMOS chip that integrates DNA sensor arrays with electronics for transduction, amplification, digital conver- sion, and signal readout. —Krishnendu Chakrabarty, Duke University Biochips 0740-7475/07/$25.00 G 2007 IEEE Copublished by the IEEE CS and the IEEE CASS IEEE Design & Test of Computers 38