The Loc Lab On A Chip Technology Biology Essay

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The ability to perform multiple laboratory operations on a small scale using miniaturized devices is very appealing. Lab-on-a-chip devices, more formally known as "Micro Total Analysis Systems" (µTAS) are micro fluidics-based systems which integrate multiple laboratory-type capabilities on a single chip only a few centimetres in size. Among their uses are real-time polymerase chain reactions (used to amplify small DNA strands into more manageable samples), immunoassays, which diagnose diseases based on antigen/antibody presence, dielectrophoresis, used to detect certain cell types, and blood sample preparation, such as the extraction of DNA from red blood cells.

INTRODUCTION

Lab-on-a-chip research can be considered as a subset of MEMS (microelectromechanical systems), and consists of many components that came out of MEMS research: micropumps, capillaries, valves, sensors, levers, and so on. Designing and fabricating such microchip systems is extremely challenging, but physicists and engineers are working upon to construct highly integrated and compact labs on chips with exciting functionalities. The collection also highlights recent advances in the application of microfluidic-chip-based technologies such as chemical synthesis, the study of complex cellular processes and medical diagnostics. For various purposes there are distinct chip test available such as DNA microarrays, GeneChip, .DNA microarrays are used to measure the expression levels of large numbers of genes simultaneously or to genotype multiple regions of a genome. Since an array is integrated with tens of thousands of probes, a microarray experiment can accomplish many genetic tests in parallel. Therefore arrays have dramatically accelerated many types of investigation. The GeneChip helps to identify the presence or absence of various different animal species in any food products, thus concerning about public health along with economic, religious and legal aspects .It works by detection of DNA sequences specific to an animal. . The beneficiaries of this technology, Lab-on-a-Chip include biotechnology, chemistry, pharmacy and research.

TECHNOLOGY

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The term Lab-on-a-Chip itself says that the technology is based on a chip (integrated circuit). An integrated circuit or monolithic integrated circuit is a set of electronic circuits on one small plate ("chip") of semiconductor material, normally silicon. The basis for most LOC fabrication processes is photolithography. Microelectromechanical system (MEMS) is the technology of very small devices. It merges at the nano-scale into nanoelectromechanical systems (NEMS) and nanotechnology. MEMS are also referred to as micro machines (in Japan), or micro systems technology - MST (in Europe).They usually consist of a central unit that processes data (the microprocessor) and several components that interact with the outside such as micro sensors. At these size scales, the standard constructs of classical physics are not always useful. Because of the large surface area to volume ratio of MEMS, surface effects such as electrostatics and wetting dominate over volume effects such as inertia or thermal mass.

Lab-on-a-Chip technology is based on microfluidics, a technique that allows samples of fluids to be prepared and analysed within the confines of a microchip. Microfluidics deals with the behaviour, precise control and manipulation of fluids that are geometrically constrained to a small, typically sub-millimeter scale. Typically fluids are moved, mixed, separated or otherwise processed. The chip itself consists of a network of tiny channels manufactured in glass that serve as pathways for the movement of fluid samples. Active microfluidics refers to the defined manipulation of the working fluid by active micro components as micropumps or micro valves. Fluids move as voltage gradients are created across the fluid, simulating the action of much larger valves and pumps. Micro pumps supply fluids in a continuous manner or are used for dosing. Micro valves determine the flow direction or the mode of movement of pumped liquids. When the chip is loaded with samples and placed in the bioanalyzer, electrodes attached to the lid of the analyser sit down into fluid wells on the chip, and testing begins. LabChips are available to analyze protein, DNA, and RNA in fluid samples. The analysis of the sample takes place as fluids are moving through the chip in a process called electrophoresis. Prior to the Lab-on-a-Chip, electrophoresis was done by molecular biologists applying samples by hand to gel-covered plates. After several hours, the proteins or nucleic acid molecules separated into visible bands on the surface of the gel. The bands were then read by visual inspection. This process has some serious disadvantages: it is tedious, subjective and subject to potential variations from one lab to the next.

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Numerous applications employ passive fluid control techniques like capillary forces. In some applications external actuation means are additionally used for a directed transport of the media. Examples are rotary drives applying centrifugal forces for the fluid transport on the passive chips.

Often processes which are normally carried out in a lab are miniaturized on a single chip in order to enhance efficiency and mobility as well as reducing sample and reagent volumes.

It is a multidisciplinary field intersecting engineering, physics, chemistry, microtechnology and biotechnology, with practical applications to the design of systems in which such small volumes of fluids will be used. Microfluidics is used in the development of inkjet print heads, DNA chips, lab-on-a-chip technology, micro-propulsion, and micro-thermal technologies.

Another biochip known as a DNA microarray is a collection of microscopic DNA spots stuck to a solid surface. Each DNA spot has picomoles (10−12 moles) of a specific DNA sequence, known as probes (or reporters or oligos). These may be a short section of a gene or other DNA element that are used to hybridize a cDNA or cRNA (also called anti-sense RNA) sample (called target) under high-stringency conditions. Probe-target hybridization is often detected and quantified by detection of fluorophore or silver labelled targets to determine relative abundance of nucleic acid sequences in the target. The main principle behind microarrays is hybridization between two DNA strands, the property of complementary nucleic acid sequences to specifically pair with one other by forming hydrogen bonds between complementary nucleotide base pairs. A high number of complementary base pairs in a nucleotide sequence mean tighter non-covalent bonding between the two strands. After washing off of non-specific bonding sequences, only the ones strongly paired strands will remain hybridized. Fluorescently labelled target sequences that bind to a probe sequence generate a signal that depends on the hybridization conditions (such as temperature), and washing after hybridization. Total strength of the signal, from a feature (spot), depends upon the amount of target sample binding to the probes present on that spot. Microarrays use relative quantization in which the intensity of a feature is compared to the intensity of the same feature under a different condition, and the identity of the feature is retrieved by its position.

In standard microarrays, the probes are synthesized and then attached via surface engineering to a solid surface by a covalent bond to a chemical matrix (via epoxy-silane, amino-silane, lysine, polyacrylamide or others). The solid surface can either be glass or a silicon chip. Other microarray platforms, such as Illumina, use microscopic beads, instead of the large solid support. Alternatively, microarrays can be made or constructed by the direct synthesis of oligonucleotide probes on solid surfaces. DNA arrays differ from other kinds of microarray only in that they either measure DNA or use DNA as part of its detection system. DNA microarrays can be used to measure changes in expression levels, to detect or find single nucleotide polymorphisms (SNPs), or to genotype or targeted re-sequencing. Microarrays also differ in fabrication, , accuracy, efficiency, workings and cost . Additional factors for microarray experiments are the experimental design and the methods or ways of analysing the data.

APPLICATIONS IN REAL-LIFE

Easy Ready ID GeneChip

It is Easy, Cost-Effective, and Fast. Any presence of DNA from GMOs, allergens, or animal by-products will trigger a colour change in the EasyRead ID GeneChip that will be seen plain as day. The absence of coloured spots on the chip is clear and documented proof of product integrity.

With the EasyRead ID GeneChip technology, detection of these regulated ingredients is now within easy and affordable reach. With this chip, product quality is assured to the highest standard because it has passed the toughest test: PCR screening. This new leading-edge technology just made the best testing easier, much faster and more economical as well. [1] 

FoodExpert-ID

FoodExpert-ID, developed by bioMérieux, is the first molecular high-density multi-detection test designed specifically for the food and feed industries. Dr. Christophe Mérieux, Vice President and Director of Medical Affairs and Research at bioMérieux said that the new test, FoodExpert-ID, is a real breakthrough for the food and feed industries. By providing rapid multi-species identification, FoodExpert-ID will help to improve the safety of food for human and animal consumption, thereby contributing to consumer health protection. Changes in food and feed legislation are creating new needs and imposing new constraints on these industries. FoodExpert-ID responds to these requirements by ensuring accurate labelling and allowing complete traceability throughout the industrial process, from animal feed to the end products released from production sites. The new test will help the food and feed industries comply with European and US legislation, by determining the species composition of a product using the latest advances in molecular biology.

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Using highly innovative techniques and providing extremely accurate results, FoodExpert-ID will change the way food and feed analysis can be achieved. The FoodExpert-ID offer is based on a high-density DNA chip, the GeneChip, developed by Affymetrix, which supports 80,000 oligonucleotide probes specially designed by bioMérieux. FoodExpert-ID combines expertise in genetics, DNA technology, image analysis and bio-informatics, and is the result of a dedicated research programme by bioMérieux .The innovative breakthrough in FoodExpert-ID lies in the test's capacity to detect 33 different species of vertebrate, and to simultaneously identify animal products present in food and feed samples according to two taxonomic criteria: class (mammals, fish and birds) and species (beef, chicken, salmon etc.). Furthermore, FoodExpert-ID can be used to test raw foods as well as products processed at high temperatures and pressures, as is the case for some animal feed. These capabilities, therefore, go beyond conventional food analysis techniques, which can detect only a limited number of species, and which are less reliable when material from more than one species is combined into a single product.

The test report generated by the FoodExpert-ID software is based on the unique DNA signature of the product. This report constitutes the "Identity Card" of the animal species entering into the composition of the product, thereby providing an invaluable tool to ensure labelling accuracy. FoodExpert-ID contributes to traceability and quality assurance in the food and feed industry through species identification at every step of the manufacturing chain "from farm to fork". [2] 

Three controls are integrated into the analysis process to verify the overall analysis procedure and to detect any contamination by the environment. One of them, for example, consists of analysing a sample of known composition, to verify that the process is running correctly. Another control consists of testing a DNA-free sample; to verify the absence of environmental contamination by DNA. The critical steps in this test are fully automated: hybridization, fluorescence analysis and the interpretation of the data by algorithms, thereby ensuring unambiguous results. The final FoodExpert-ID report provides the customer with a product signature based on its DNA profile.

Detecting Species-Specific Variations

A popular method for DNA-based seafood identification is PCR-RFLP, which is based on variations in the lengths of particular restriction fragments generated from specific regions of the genome. Species-specific variations in the lengths of the fragments are analyzed by PCR amplification of specific DNA regions. The amplicons are then digested with restriction enzymes, and the lengths of the digested fragments are determined by gel electrophoresis, resulting in species-specific restriction profiles.

The profiles are compared with reference samples for species identification. This procedure has been widely used in seafood authentication because it is less costly, simpler, and more suitable for routine laboratory analysis than techniques such as FINS or DNA barcoding, both of which are based on DNA sequencing analysis. PCR-RFLP is a relatively rapid, reproducible, and robust laboratory technique that does not require expensive equipment, and it is approved in many countries for the determination of seafood species. PCR-RFLP is therefore well suited for fish species detection, particularly for use closer to the origin of the sample.

Researchers at Campden BRI in England have developed a PCR-RFLP method that replaces the gel electrophoresis step with microfluidic lab-on-a-chip technology, utilizing CE to analyze DNA fragments. [3] Lab-on-a-chip CE increases the ease of use, sensitivity, speed, and reliability of PCR-RFLP compared to gel-based methods. [4] The chips are single-use units that contain etched capillaries attached directly to sample loading wells.

The electrophoretic analysis and interpretation of results are completely automated, requiring only the click of a mouse after the samples are loaded onto the chip. The superior resolution of lab-on-a-chip technology enables the detection of DNA fragments that may be too small for visualization using gel electrophoresis. While the visual inspection of agarose gels and comparison to validated fish species patterns is tedious and error-prone, the lab-on-a-chip system automatically analyses the pattern, compares it to a database of validated fish species patterns, and generates a species match. The database is expandable to thousands of species, assuring that this testing platform will be able to adapt to future needs.

Schematic diagram of the Agilent Technologies lab-on-a-chip technology used to perform fish species identification utilizing polymerase chain reaction-restriction fragment length polymorphism.

REP

Researchers have demonstrated a new technology that combines a laser and electric fields to create tiny centrifuge-like whirlpools to separate particles and microbes by size, a potential lab-on-a-chip system for medicine and research. Here the technique is used to collect a bacterium called Shewanella oneidensis.

REP is a potential new tool for applications including medical diagnostics; testing food, water and contaminated soil; isolating DNA for gene sequencing; crime-scene forensics; and pharmaceutical manufacturing. [5] 

DNA microarrays

DNA microarrays can be used to detect DNA (as in comparative genomic hybridization), or detect RNA (most commonly as cDNA after reverse transcription) that may or may not be translated into proteins. The process of measuring gene expression via cDNA is called expression analysis or expression profiling.

LOC in Plant Sciences

Lab-on-a-chip devices could be used to characterize pollen tube guidance in Arabidopsis [6] thaliana. Specifically, plant on a chip is a miniaturized device in which pollen tissues and ovules could be incubated for plant sciences studies.

ADVANTAGES OF LOCs

LOCs provide various advantages, which are specific to their applications. One of the greatest advantages to the lab-on-a-chip is its small size, which allows for mass production and a reduced need for expensive substances sometimes necessary for certain types of lab work and low fluid volumes consumption (less waste, lower reagents costs and less required sample volumes for diagnostics). The time taken to synthesize and analyse a product is reduced. Hence, better process control because of a faster response of the system (e.g. thermal control for exothermic chemical reactions).

The unique behaviour of liquids at the micro scale allows greater control of molecular concentrations and interactions and reagent costs and the amount of chemical waste can be much reduced.

The faster analysis and response times due to short diffusion distances results in fast heating and a high surface to volume ratios along with small heat capacities.

The compactness of the systems due to integration of much functionality and small volumes makes the technology easy to use and implement.

The compactness also results in massive parallelization, which allows high-throughput analysis and this is very much practically applicable in complex tasks.

The lower fabrication cost allows the production of cost-effective disposable chips. Thus LOCs are fabricated in mass production.

It also provides a safer platform for chemical, radioactive or biological studies because of integration of functionality, smaller fluid volumes and stored energies. Research is also made easier.

This combination of tools and information enables an approach called hypothesis-driven research. Such research gives scientists the flexibility to modify experimental design based on the outcome of previous experiments, thus taking some of the guesswork out of the lengthy drug development process. Laboratories that are applying the new miniaturized technology are already seeing reductions research time and cost with improved efficiency and analysis quality. [7] 

DISADVANTAGES OF LOCs

A few disadvantages falling in this technology are that since it is a novel technology it is not yet fully developed.

The physical and chemical effects-like capillary forces, surface roughness, chemical interactions of construction materials on reaction processes-become more dominant on small-scale. This can sometimes make processes in LOCs more complex than in conventional lab equipment.

The detection principles may not always scale down in a positive way, leading to low signal-to-noise ratios affecting the outcome.

Although the absolute geometric accuracies and precision in microfabrication are high, they are often rather poor in a relative way, compared to precision engineering for instance.

CHALLENGES

Even though LOCs provide evident useful applications in various fields, there are numerous challenges with the scaling down of traditional chemical principles, meaning that lab-on-a-chip systems may require some re-engineering to match the functionality of their larger counterparts. The arrival of inexpensive microarray experiments created many specific bioinformatics challenges such as experimental design, statistical analysis, , standardization, relation between gene and probe, and data warehousing.

Experimental design (the multiple levels of replication in experimental design)

The considerations of experimental design are of critical importance if statistically and biologically valid conclusions are to be drawn from the data because of the biological complexity of gene expression; there are three main elements to consider when designing a microarray experiment. First, replication of the biological samples is essential for drawing conclusions from the experiment. Second, technical replicates (two RNA samples obtained from each experimental unit) help to guarantee precision and allow for testing differences within treatment groups. The biological replicates include independent RNA extractions and technical replicates may be two aliquots of the very same extraction. Third, spots of each cDNA clone or oligonucleotide are present as replicates (at least duplicates) on the microarray slide, to provide an estimate of technical precision in each hybridization. It is critical that information about the sample preparation and handling is discussed, in order to help identify the independent units in the experiment and to avoid distended estimates of statistical significance. [8] 

Statistical Analysis (the treatment of the data)

Microarray data sets are commonly quite large, and analytical precision is swayed by a number of variables. The statistical challenges include taking into account effects of background noise and suitable normalization of the data. Normalization methods may be suited to particular platforms and, in the case of commercial platforms, the analysis may be proprietary. Statistical analysis is affected by the following algorithms:

Image analysis algorithm: gridding, spot recognition of the scanned image (segmentation algorithm), removal or marking of poor-quality and low-intensity features (called flagging).

Data processing algorithm: background subtraction (based on global or local background), determination of spot intensities and intensity ratios, visualisation of data (e.g. see MA plot), and log-transformation of ratios, global or local normalization of intensity ratios, and segmentation into different copy number regions using step detection algorithms. [9] 

Recognition of statistically significant changes: t-test, ANOVA, Bayesian method [10] Mann-Whitney test methods tailored to microarray data sets, which take into account multiple comparisons or cluster analysis. These methods assess statistical power based on the variation present in the data and the number of experimental replicates, and can help minimize Type I and Type II errors in the analyses. [11] 

Network-based methods: Statistical methods that take the underlying structure of gene networks into account, representing either associative or causative interactions or dependencies among gene products.

Microarray data may require further processing aimed at reducing the dimensionality of the data to assist comprehension and more focused analysis. Other methods allow analysis of data consisting of a lesser number of biological or technical replicates; for e.g., the Local Pooled Error (LPE) test pools standard deviations of genes with quite similar expression levels in an effort to compensate or indemnify for insufficient replication.

Standardization (the number of platforms, data format and independent groups) Microarray data is quite difficult to exchange due to the lack of standardization in platform fabrication, assay protocols, and analysis methods. This presents an interoperability problem in bioinformatics. Various grass-roots open-source projects are trying to ease the exchange and analysis of data produced with non-proprietary chips:

For example, the "Minimum Information About a Microarray Experiment" (MIAME) checklist helps define the level of detail that should exist and is being adopted by many journals as a requirement for the submission of papers incorporating microarray results. But MIAME does not describe the format for the information, so while many formats can support the MIAME requirements, as of 2007 no format allows verification of complete semantic compliance. The "MicroArray Quality Control (MAQC) Project" is being conducted by the US Food and Drug Administration (FDA) to develop standards and quality control metrics which will eventually allow the use of MicroArray data in drug discovery, clinical practice and regulatory decision-making. [12] The MGED Society has developed standards for the representation of gene expression experiment results and relevant annotations.

Relation between gene and probe (precision and accuracy)

The relation between a probe and the mRNA that it is anticipated to detect is not trivial. Some mRNAs may cross-hybridize probes in the array that are supposed to detect another mRNA. Additionally, mRNAs may experience amplification bias that is sequence or molecule-specific. Thirdly, probes that are intended and designed to detect the mRNA of a specific gene may be relying on genomic EST information that is inaccurately associated with that gene.

Data warehousing (the absolute volume of data and the ability to share it)

Microarray data was found to be more useful when collated to other similar datasets. The sheer volume of data, specialized formats (such as MIAME), and curation efforts related to the datasets require specialized databases to store the data. A few open-source data warehousing solutions, such as InterMine and BioMart, have been created for the specific purpose of integrating diverse biological datasets, and also support analysis.

CONCLUSION

Thus, Lab-on-a Chip is an analytical technology replacing the traditional methods such as gel electrophoresis or capillary electrophoresis used in determination of quality, size and concentration of biomolecules such as DNA,RNA,and proteins. It outshines the conventional techniques by having a minimal sample requirement, rapid analysis times, minimal exposure to health-hazard materials and most important the ease-of-use.

Basically, this technology allows for downscaling and integration of several experimental steps into one single process, along with automated data analysis.

Lab-on-a-chip technology may soon become an important part of efforts to improve global health [13] , particularly through the development of point-of-care testing devices. In countries with few healthcare resources, infectious diseases that would be treatable in a developed nation are often deadly. In some cases, poor healthcare clinics have the drugs to treat a certain illness but lack the diagnostic tools to identify patients who should receive the drugs. Many researchers believe that LOC technology may be the key to powerful new diagnostic instruments. The goal of these researchers is to create microfluidic chips that will allow healthcare providers in poorly equipped clinics to perform diagnostic tests such as immunoassays and nucleic acid assays with no laboratory support.

In the not-so-distant future, lab-on-a-chip systems may even be integrated into familiar devices such as laptop computers, allowing chemistry and biology students to play with scientific tools outside the traditional confines of the lab environment. Lab-on-a-chip devices could one day lead to a pinhead-sized implant or skin-mounted device able to almost instantly detect the presence of disease bacteria or biochemical agents in the bloodstream. In the future, doctors may be able to make diagnoses quickly and accurately using information transmitted from such a device.