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ABSTRACT
A biochip is a collection of miniaturized test sites (microarrays) arranged on a solid substrate that permits many tests to be performed at the same time in order to achieve higher throughput and speed. Like a computer chip that can perform millions of mathematical operations in one second, a biochip can perform thousands of biological reactions, such as decoding genes, in a few seconds. Biochips helped to dramatically accelerate the identification of the estimated 80,000 genes in human DNA, an ongoing world-wide research collaboration known as the Human genome project. Developing a biochip plat-form incorporates electronics for addressing, reading out, sensing and controlling temperature and, in addition, a handheld analyzer capable of multiparameter identification. The biochip platform can be plugged in a peripheric standard bus of the analyzer device or communicate through a wireless channel. Biochip technology has emerged from the fusion of biotechnology and micro/nanofabrication technology. Biochips enable us to realize revolutionary new bioanalysis systems that can directly manipulate and analyze the micro/nano-scale world of biomolecules, organelles and cells.
INTRODUCTION
What is a biochip?
A biochip is a collection of miniaturized test sites (microarrays) arranged on a solid substrate that permits many tests to be performed at the same time in order to achieve higher throughput and speed. Typically, a biochip's surface area is no larger than a fingernail. Like a computer chip that can perform millions of mathematical operations in one second, a biochip can perform thousands of biological reactions, such as decoding genes, in a few seconds. Biochip is a broad term indicating the use of microchip technology in molecular biology and can be defined as arrays of selected biomolecules immobilized on a surface. Biochip will also be used in animal and plant breeding, and in the monitoring of foods and the environment. Biochip is a small-scale device, analogous to an integrated circuit, constructed of or used to analyze organic molecules associated with living organisms. One type of theoretical biochip is a small device constructed of large organic molecules, such as proteins, and capable of performing the functions (data storage, processing) of an electronic computer. The other type of biochip is a small device capable of performing rapid, small-scale biochemical reactions for the purpose of identifying gene sequences, environmental pollutants, airborne toxins, or other biochemical constituents.
HISTORY/GENERATION
The development of biochips has a long history, starting with early work on the underlying sensor technology. One of the first portable, chemistry-based sensors was the glass pH electrode, invented in 1922 by Hughes (Hughes, 1922). Measurement of pH was accomplished by detecting the potential difference developed across a thin glass membrane selective to the permeation of hydrogen ions; this selectivity was achieved by exchanges between H+ and SiO sites in the glass. The basic concept of using exchange sites to create perm selective membranes was used to develop other ion sensors in subsequent years. For example, a K+ sensor was produced by incorporating valinomycin into a thin membrane (Schultz, 1996). Over thirty years elapsed before the first true biosensor (i.e. a sensor utilizing biological molecules) emerged. In 1956, Leland Clark published a paper on an oxygen sensing electrode(Clark, 1956_41). This device became the basis for a glucose sensor developed in 1962 by Clark and colleague Lyons which utilized glucose oxidase molecules embedded in a dialysis membrane (Clark, 1962). The enzyme functioned in the presence of glucose to decrease the amount of oxygen available to the oxygen electrode, thereby relating oxygen levels to glucose concentration. This and similar biosensors became known as enzyme electrodes, and are still in use today.
In 1953, Watson and Crick announced their discovery of the now familiar double helix structure of DNA molecules and set the stage for genetics research that continues to the present day (Nelson, 2000). The development of sequencing techniques in 1977 by Gilbert (Maxam, 1977) and Sanger (Sanger, 1977) (working separately) enabled researchers to directly read the genetic codes that provide instructions for protein synthesis. This research showed how hybridization of complementary single oligonucleotide strands could be used as a basis for DNA sensing. Two additional developments enabled the technology used in modern DNA-based biosensors. First, in 1983 Kary Mullis invented the polymerase chain reaction (PCR) technique (Nelson, 2000), a method for amplifying DNA concentrations. This discovery made possible the detection of extremely small quantities of DNA in samples. Second, in 1986 Hood and co-workers devised a method to label DNA molecules with fluorescent tags instead of radiolabels (Smith, 1986), thus enabling hybridization experiments to be observed optically.
The rapid technological advances of the biochemistry and semiconductor fields in the 1980s led to the large scale development of biochips in the 1990s. At this time, it became clear that biochips were largely a "platform" technology which consisted of several separate, yet integrated components. Figure 1 shows the make up of a typical biochip platform. The actual sensing component (or "chip") is just one piece of a complete analysis system. Transduction must be done to translate the actual sensing event (DNA binding, oxidation/reduction, etc.) into a format understandable by a computer (voltage, light intensity, mass, etc.), which then enables additional analysis and processing to produce a final, human-readable output. The multiple technologies needed to make a successful biochip — from sensing chemistry, to microarraying, to signal processing — require a true multidisciplinary approach, making the barrier to entry steep. One of the first commercial biochips was introduced by Affymetrix. Their "GeneChip" products contain thousands of individual DNA sensors for use in sensing defects, or single nucleotide polymorphisms (SNPs), in genes such as p53 (a tumor suppressor) and BRCA1 and BRCA2 (related to breast cancer) (Cheng, 2001). The chips are produced using microlithography techniques traditionally used to fabricate integrated circuits