INTRODUCTION

The development of biochips is a major thrust of the rapidly growing biotechnology industry, which encompasses a very diverse range of research efforts including genomics, proteomics, and pharmaceuticals, among other activities. The merging of these two fields in recent years has enabled biotechnologists to begin packing their traditionally bulky sensing tools into smaller and smaller spaces, onto so-called biochips. 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. A genetic biochip is designed to "freeze" into place the structures of many short strands of DNA (deoxyribonucleic acid), the basic chemical instruction that determines the characteristics of an organism. Effectively, it is used as a kind of "test tube" for real chemical samples. A specially designed microscope can determine where the sample hybridized with DNA strands in the biochip. 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. The microchip is described as a sort of "word search" function that can quickly sequence DNA. In addition to genetic applications, the biochip is being used in toxicological, protein, and biochemical research. Biochips can also be used to rapidly detect chemical agents used in biological warfare so that defensive measures can be taken.

biochips

How does a biochip work?

The "chip contains a 10 character alphanumeric identification code that is never duplicated. when a scanner is passed over the chip, the scanner emits a 'beep' and your ... number flashes in the scanner's digital display." Biochips concentrate thousands of different genetic tests on a surface area of just a few square centimeters so that they can be analyzed by computer within a very short space of time. On the one hand this makes the individual genetic tests much cheaper and on the other hand, thanks to the capacity, many more tests can be carried out. Biochips concentrate thousands of different genetic tests on a surface area of just a few square centimeters so that they can be analyzed by computer within a very short space of time. On the one hand this makes the individual genetic tests much cheaper and on the other hand, many more tests can be carried out. Affymetrix invented the high-density microarray in 1989 and has been selling this assay since 1994 under the name of Gene Chip (figure 1). In this context, microarray means that the genetic tests are organized (arrayed) in micro meters pacing(micro).As it was not previously possible to go below the millimeter range, the description high density is certainly justified. Experiments (e.g. measurement of gene activity or sequencing to demonstrate mutations and polymorphisms) that could previously only be done individually, one after the other, can now be carried out in large numbers at the same time and in a highly automated manner.

(Biochips are a platform that require, in addition to microarray technology, transduction and signal processing technologies to output the results of sensing experiments)

Applications of Biochip

3D Sarfus image of a DNA biochip.

4.1Genomics Genomics is the study of gene sequences in living organisms and being able to read and interpret them. The human genome has been the biggest project undertaken to date but there are many research projects around the world trying to map the gene sequences of other organisms. The use of Biochip facilitate: Automated genomic analysis including genotyping, gene expression DNA isolation from complex matrices with aim to increase recovery efficiency DNA amplification by optimizing the copy number DNA hybridization assays to improve speed and stringency .4.2Proteomics Proteome analysis or Proteomics is the investigation of all the proteins present in a cell, tissue or organism. Proteins, which are responsible for all biochemical work within a cell, are often the targets for development of new drugs. The use of Biochip facilitate: High throughput proteomic analysis Multi-dimensional micro separations (pre LC/MS) to achieve high plate number Electro kinetic sample injection for fast, reproducible, samples Stacking or other pre concentration methods (as a precursor to biosensors) to improve detection limits Kinetic analysis of

interactions between proteins to enable accurate, transport-free kinetics 4.3Cellomics Every living creature is made up of cells, the basic building blocks of life.. Cells are used widely by for several applications including study of drug cell interactions for drug discovery, as well as in bio sensing. The use of Biochip facilitate:
Biochip /Applications of Biochip 7

Design/develop "lab-in-cell" platforms handling single or few cells with nano probes in carefully controlled environments. Cell handling, which involve sorting and positioning of the cells optimally using DEP, optical traps etc. Field/reagent based cell lyses, where the contents of the cell are expelled out by breaking the membrane, or increase the efficiency of transfaction using reagents/field Intracellular processes to obtain high quality safety/toxicity ADME/T data 4.4Biodiagnostics and (Nano) Biosensors Bio diagnostics or bio sensing is the field of sensing biological molecules based on electrochemical, biochemical, optical, luminometric methods. The use of Biochip facilitate: Genetic/Biomarker Diagnostics, development of Bio warfare sensors which involves optimization of the platform, reduction in detection time and improving the signal-to-noise ratio Selection of detection platform where different formats such as lateral flow vs. micro fluidics are compared for ease/efficiency Incorporation of suitable sensing modality by evaluating tradeoffs and down select detection modes(colour / luminometric, electrochemical, biochemical, optical methods) for specific need. 4.5 Protein Chips for Diagnosis and Analysis of Diseases The Protein chip is a micro-chip with its surface modified to detect various disease causing proteins simultaneously in order to help find a cure for them. Bio-chemical materials such as antibodies responding to proteins, receptors, and nucleic acids are to be fixed to separate and analyze protein.

Human interface to Biochip

Biochips provide interfaces between living systems and electro-mechanical and computational devices. These chips may be used in such varied applications as artificial sensors, prosthesis, portable/disposable laboratories or even as implantable devices to enhance human life. Biochips promise dramatic changes in future medical science and human life in general. With the advances of bio and nano technologies two strong paradigms of integrated electronic and life are emerging. Biosensor chips can provide the construction of sophisticated human sensing systems such as nose and ears. The second paradigm is chips for sensing biology that will provide for interactions with living bodies and build new diagnosis tools (such as diabetes glucose meters) or new medicines (such as a bio-assay chip). A tiny microchip, the size of a grain of rice, is simply placed under the skin. It is so designed as to be injected simultaneously with a vaccination or alone." The biochip is inserted into the subject with a hypodermic syringe. Injection is safe and simple, comparable to common vaccines. Anesthesia is not required nor recommended. In dogs and cats, the biochip is usually injected behind the neck between the shoulder blades. Trovan, Ltd., markets an implant, featuring a patented "zip quill",

which you simply press in, no syringe is needed. According to AVID "Once implanted, the identity tag is virtually impossible to retrieve. . . The number can never be altered."

Human interfacing of Biochip

The syringe used is of a normal size seringe & the chip can be placed below the skin layer very easily.

Fig 5.2 Syringe to implant Biochip

ADVANTAGES & DISADVANTAGES

Advantages

.The ability to detect multiple viral agents in parallel e.g. differential diagnosis of agents from other diseases that cause similar clinical symptoms, or the recognition of complex mixtures of agents. .Clarification of syndromes of unknown a etiology .Increase speed of diagnosis of unknown pathogens ("future proofed" surveillance tools).

.Viral typing (AIV, FMDV, Rabies) .Drive policy for diagnostics and disease control. .Epidemiological tracing .Interagency collaboration. The consortium consists of National, EU and OIE reference laboratories and has access to real sample material from a wide selection of hosts and viruses.
Disadvantages

.These methods have problems that a DNA chip cannot be fabricated at high density and mass production is limited. Thus, these methods are applicable to fabrication of a DNA chip for study. .Meanwhile, the DNA chip and the DNA microarray have different fabrication methods but are similar in that different oligonucleotides are aligned on a square spot having a certain size in a check pattern.

CONCLUSION
Biochips are fast, accurate, miniaturized, and can be expected to become economically advantageous attributes that make them analogous to a computer chip. One expects to see an accelerated trend of ultra miniaturization, perhaps involving entirely novel media, and an increased ability to analyze not only genetic material but also other types of biologic molecules. One expects, too, an eventual harmonization of technologies, so that dominant fabrication strategies will emerge, at least for certain types of applications, including a favored format for genetic analysis and another for antibodies and other proteins. Since the potential applications are vast, both for research and for clinical use, the potential markets for biochips will be huge, a powerful driving force for their continued development . REFERENCES

1. Marshall,A., Hodgson, J., DNA chips: An array of possibilities, Nature Biotechnology, 1998, 16: 27. 2. Kricha, L.J., Miniaturization of analytical systems, Clinical Chemistry, 1998, 44 : 2088. 3. Vahid Bemanian, Frydis D. Blystad, Live Bruseth, Gunn A. Hildrestrand, Lise Holden, Endre Kjrland, Pl Puntervoll, Hanne Ravneberg and Morten Ruud, "What is

Bioethics?" Dec 1998. 4. Fan et al. (2009). "Two-Dimensional Electrophoresis in a Chip". Lab-on-a-Chip Technology: Biomolecular Separation and Analysis. Caister Academic. 5. Herold, KE; Rasooly, A (editor) (2009). Lab-on-a-Chip Technology: Fabrication and Microfluidics

Microarray fabrication

3D Sarfus image of a DNA biochip. The microarray the dense, two-dimensional grid of biosensors is the critical component of a biochip platform. Typically, the sensors are deposited on a flat substrate, which may either be passive (e.g. silicon or glass) or active, the latter consisting of integrated electronics or micromechanical devices that perform or assist signal transduction. Surface chemistry is used to covalently bind the sensor molecules to the substrate medium. The fabrication of microarrays is non-trivial and is a major economic and technological hurdle that may ultimately decide the success of future biochip platforms. The primary manufacturing challenge is the process of placing each sensor at a specific position (typically on a Cartesian grid) on the substrate. Various means exist to achieve the placement, but typically robotic micro-pipetting (Schena, 1995) or microprinting (MacBeath, 1999) systems are used to place tiny spots of sensor material on the chip surface. Because each sensor is unique, only a few spots can be placed at a time. The low-throughput nature of this process results in high manufacturing costs. Fodor and colleagues developed a unique fabrication process (later used by Affymetrix) in which a series of microlithography steps is used to combinatorially synthesize hundreds of thousands of unique, single-stranded DNA sensors on a substrate one nucleotide at a time (Fodor, 1991; Pease, 1994). One lithography step is needed per base type; thus, a total of

four steps is required per nucleotide level. Although this technique is very powerful in that many sensors can be created simultaneously, it is currently only feasible for creating short DNA strands (1525 nucleotides). Reliability and cost factors limit the number of photolithography steps that can be done. Furthermore, light-directed combinatorial synthesis techniques are not currently possible for proteins or other sensing molecules. As noted above, most microarrays consist of a Cartesian grid of sensors. This approach is used chiefly to map or "encode" the coordinate of each sensor to its function. Sensors in these arrays typically use a universal signalling technique (e.g. fluorescence), thus making coordinates their only identifying feature. These arrays must be made using a serial process (i.e. requiring multiple, sequential steps) to ensure that each sensor is placed at the correct position. "Random" fabrication, in which the sensors are placed at arbitrary positions on the chip, is an alternative to the serial method. The tedious and expensive positioning process is not required, enabling the use of parallelized self-assembly techniques. In this approach, large batches of identical sensors can be produced; sensors from each batch are then combined and assembled into an array. A non-coordinate based encoding scheme must be used to identify each sensor. As the figure shows, such a design was first demonstrated (and later commercialized by Illumina) using functionalized beads placed randomly in the wells of an etched fiber optic cable (Steemers, 2000; Michael, 1998) Each bead was uniquely encoded with a fluorescent signature. However, this encoding scheme is limited in the number of unique dye combinations that can be used and successfully differentiated.

Protein biochip array and other microarray technologies

Microarrays are not limited to DNA analysis; protein microarrays, antibody microarray, chemical compound microarray can also be produced using biochips. Randox Laboratories Ltd. launched Evidence, the first protein Biochip Array Technology analyzer in 2003. In protein Biochip Array Technology, the biochip replaces the ELISA plate or cuvette as the reaction platform. The biochip is used to simultaneously analyze a panel of related tests in a single sample, producing a patient profile. The patient profile can be used in disease screening, diagnosis, monitoring disease progression or monitoring treatment. Performing multiple analyses simultaneously, described as multiplexing, allows a significant reduction in processing time and the amount of patient sample required. Biochip Array Technology is a novel application of a familiar methodology, using sandwich, competitive and antibodycapture immunoassays. The difference from conventional immunoassays is that the capture ligands are covalently attached to the surface of the biochip in an ordered array rather than in solution. In sandwich assays an enzyme-labelled antibody is used; in competitive assays an enzymelabelled antigen is used. On antibody-antigen binding a chemiluminescence reaction produces light. Detection is by a charge-coupled device (CCD) camera. The CCD camera is a sensitive and high-resolution sensor able to accurately detect and quantify very low levels of light. The test regions are located using a grid pattern then the chemiluminescence

signals are analysed by imaging software to rapidly and simultaneously quantify the individual analytes.