Lab-on-a-chip - AbsoluteAstronomy.com

A lab-on-a-chip is a device that integrates one or several laboratory

Laboratory

A laboratory is a facility that provides controlled conditions in which scientific research, experiments, and measurement may be performed. The title of laboratory is also used for certain other facilities where the processes or equipment used are similar to those in scientific laboratories...

functions on a single chip

Integrated circuit

An integrated circuit or monolithic integrated circuit is an electronic circuit manufactured by the patterned diffusion of trace elements into the surface of a thin substrate of semiconductor material...

of only millimeters to a few square centimeters in size. LOCs deal with the handling of extremely small fluid volumes down to less than pico liters. Lab-on-a-chip devices are a subset of MEMS

Microelectromechanical systems

Microelectromechanical systems is the technology of very small mechanical devices driven by electricity; it merges at the nano-scale into nanoelectromechanical systems and nanotechnology...

devices and often indicated by "Micro Total Analysis Systems" (µTAS) as well. Microfluidics

Microfluidics

Microfluidics deals with the behavior, precise control and manipulation of fluids that are geometrically constrained to a small, typically sub-millimeter, scale.Typically, micro means one of the following features:* small volumes...

is a broader term that describes also mechanical flow control devices like pumps and valves or sensors like flowmeters and viscometers. However, strictly regarded "Lab-on-a-Chip" indicates generally the scaling of single or multiple lab processes down to chip-format, whereas "µTAS" is dedicated to the integration of the total sequence of lab processes to perform chemical analysis. The term "Lab-on-a-Chip" was introduced later on when it turned out that µTAS technologies were more widely applicable than only for analysis purposes.

History

After the invention of microtechnology

Microtechnology

Microtechnology is technology with features near one micrometre .In the 1960s, scientists learned that by arraying large numbers of microscopic transistors on a single chip, microelectronic circuits could be built that dramatically improved performance, functionality, and reliability, all while...

(~1954) for realizing integrated semiconductor

Semiconductor

A semiconductor is a material with electrical conductivity due to electron flow intermediate in magnitude between that of a conductor and an insulator. This means a conductivity roughly in the range of 103 to 10−8 siemens per centimeter...

structures for microelectronic chips, these lithography

Lithography

Lithography is a method for printing using a stone or a metal plate with a completely smooth surface...

-based technologies were soon applied in pressure sensor manufacturing (1966) as well. Due to further development of these usually CMOS

CMOS

Complementary metal–oxide–semiconductor is a technology for constructing integrated circuits. CMOS technology is used in microprocessors, microcontrollers, static RAM, and other digital logic circuits...

-compatibility limited processes, a tool box became available to create micrometre or sub-micrometre sized mechanical structures in silicon wafers as well: the Micro Electro Mechanical Systems (MEMS

Microelectromechanical systems

Microelectromechanical systems is the technology of very small mechanical devices driven by electricity; it merges at the nano-scale into nanoelectromechanical systems and nanotechnology...

) era (also indicated with Micro System Technology - MST) had started.

Next to pressure sensors, airbag sensors and other mechanically movable structures, fluid handling devices were developed. Examples are: channels (capillary connections), mixers, valves, pumps and dosing devices. The first LOC analysis system was a gas chromatograph, developed in 1975 by S.C. Terry - Stanford University. However, only at the end of the 1980s, and beginning of the 1990s, the LOC research started to seriously grow as a few research groups in Europe developed micropumps, flowsensors and the concepts for integrated fluid treatments for analysis systems. These µTAS concepts demonstrated that integration of pre-treatment steps, usually done at lab-scale, could extend the simple sensor functionality towards a complete laboratory analysis, including e.g. additional cleaning and separation steps.

A big boost in research and commercial interest came in the mid 1990’s, when µTAS technologies turned out to provide interesting tooling for genomics

Genomics

Genomics is a discipline in genetics concerning the study of the genomes of organisms. The field includes intensive efforts to determine the entire DNA sequence of organisms and fine-scale genetic mapping efforts. The field also includes studies of intragenomic phenomena such as heterosis,...

applications, like capillary electrophoresis

Capillary electrophoresis

Capillary electrophoresis , also known as capillary zone electrophoresis , can be used to separate ionic species by their charge and frictional forces and hydrodynamic radius. In traditional electrophoresis, electrically charged analytes move in a conductive liquid medium under the influence of an...

and DNA microarrays. A big boost in research support also came from the military, especially from DARPA (Defense Advanced Research Projects Agency), for their interest in portable bio/chemical warfare agent detection systems. The added value was not only limited to integration of lab processes for analysis but also the characteristic possibilities of individual components and the application to other, non-analysis, lab processes. Hence the term "Lab-on-a-Chip" was introduced.

Although the application of LOCs is still novel and modest, a growing interest of companies and applied research groups is observed in different fields such as analysis (e.g. chemical analysis, environmental monitoring, medical diagnostics and cellomics) but also in synthetic chemistry (e.g. rapid screening and microreactors for pharmaceutics). Besides further application developments, research in LOC systems is expected to extend towards downscaling of fluid handling structures as well, by using nanotechnology

Nanotechnology

Nanotechnology is the study of manipulating matter on an atomic and molecular scale. Generally, nanotechnology deals with developing materials, devices, or other structures possessing at least one dimension sized from 1 to 100 nanometres...

. Sub-micrometre and nano-sized channels, DNA labyrinths, single cell detection and analysis, and nano-sensors, might become feasible, allowing new ways of interaction with biological species and large molecules. Many books have been written that cover various aspects of these devices, including the fluid transport, system properties, and bioanalytical applications.

Chip materials and fabrication technologies

The basis for most LOC fabrication processes is photolithography

Photolithography

Photolithography is a process used in microfabrication to selectively remove parts of a thin film or the bulk of a substrate. It uses light to transfer a geometric pattern from a photomask to a light-sensitive chemical "photoresist", or simply "resist," on the substrate...

. Initially most processes were in silicon, as these well-developed technologies were directly derived from semiconductor

Semiconductor

fabrication. Because of demands for e.g. specific optical characteristics, bio- or chemical compatibility, lower production costs and faster prototyping, new processes have been developed such as glass, ceramics and metal etching, deposition and bonding, PDMS

PDMS

PDMS may refer to:* Palm Desert Middle School, a middle school in Palm Desert, California* Parliamentary Document Management System, a system used by several government departments in Australia for workflow/document management...

processing (e.g., soft lithography

Soft lithography

), thick-film- and stereolithography

Stereolithography

Stereolithography is an additive manufacturing technology for producing models, prototypes, patterns, and in some cases, production parts.-Technology description:...

as well as fast replication methods via electroplating

Electroplating

Electroplating is a plating process in which metal ions in a solution are moved by an electric field to coat an electrode. The process uses electrical current to reduce cations of a desired material from a solution and coat a conductive object with a thin layer of the material, such as a metal...

, injection molding

Injection molding

Injection molding is a manufacturing process for producing parts from both thermoplastic and thermosetting plastic materials. Material is fed into a heated barrel, mixed, and forced into a mold cavity where it cools and hardens to the configuration of the cavity...

and embossing. Furthermore the LOC field more and more exceeds the borders between lithography-based microsystem technology, nano technology and precision engineering.

Advantages of LOCs

LOCs may provide advantages, which are specific to their application. Typical advantages are:

low fluid volumes consumption (less waste, lower reagents costs and less required sample volumes for diagnostics)
faster analysis and response times due to short diffusion distances, fast heating, high surface to volume ratios, small heat capacities.
better process control because of a faster response of the system (e.g. thermal control for exothermic chemical reactions)
compactness of the systems due to integration of much functionality and small volumes
massive parallelization due to compactness, which allows high-throughput analysis
lower fabrication costs, allowing cost-effective disposable chips, fabricated in mass production
safer platform for chemical, radioactive or biological studies because of integration of functionality, smaller fluid volumes and stored energies

Disadvantages of LOCs

Some of the disadvantages of LOCs are:

novel technology and therefore not yet fully developed
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
detection principles may not always scale down in a positive way, leading to low signal-to-noise ratio
Signal-to-noise ratio
Signal-to-noise ratio is a measure used in science and engineering that compares the level of a desired signal to the level of background noise. It is defined as the ratio of signal power to the noise power. A ratio higher than 1:1 indicates more signal than noise...

s
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.

Examples of LOC Applications

Real-time PCR
Polymerase chain reaction
The polymerase chain reaction is a scientific technique in molecular biology to amplify a single or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence....

: detect bacteria, viruses and cancers.
Biochemical assays
Immunoassay
Immunoassay
An immunoassay is a biochemical test that measures the presence or concentration of a substance in solutions that frequently contain a complex mixture of substances. Analytes in biological liquids such as serum or urine are frequently assayed using immunoassay methods...

: detect bacteria, viruses and cancers based on antigen-antibody reactions.
Dielectrophoresis
Dielectrophoresis
Dielectrophoresis is a phenomenon in which a force is exerted on a dielectric particle when it is subjected to a non-uniform electric field. This force does not require the particle to be charged. All particles exhibit dielectrophoretic activity in the presence of electric fields...

: detection of cancer cells and bacteria.
Blood sample preparation: can lyse
Lysis
Lysis refers to the breaking down of a cell, often by viral, enzymic, or osmotic mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a "lysate"....

cells to extract DNA.
Cellular lab-on-a-chip for single-cell analysis.
Ion channel screening (patch clamp)
Testing the safety and efficacy of new drugs, as with lung on a chip
Lung on a chip
Lung on a Chip is a complex, three-dimensional model of a living, breathing human lung on a microchip. The device is made using human lung and blood vessel cells and it can predict absorption of airborne nanoparticles and mimic the inflammatory response triggered by microbial pathogens...
Manipulating Soft Matter
Soft matter
Soft matter is a subfield of condensed matter comprising a variety of physical states that are easily deformed by thermal stresses or thermal fluctuations. They include liquids, colloids, polymers, foams, gels, granular materials, and a number of biological materials...

particularly for confinement studies of colloids and cells .

LOCs and Global Health

Lab-on-a-chip technology may soon become an important part of efforts to improve global health

Global health

Global health is the health of populations in a global context and transcends the perspectives and concerns of individual nations. Health problems that transcend national borders or have a global political and economic impact, are often emphasized...

, particularly through the development of point-of-care testing

Point-of-care testing

Point-of-care testing is defined as medical testing at or near the site of patient care. The driving notion behind POCT is to bring the test conveniently and immediately to the patient. This increases the likelihood that the patient, physician, and care team will receive the results quicker,...

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

Nucleic acid

Nucleic acids are biological molecules essential for life, and include DNA and RNA . Together with proteins, nucleic acids make up the most important macromolecules; each is found in abundance in all living things, where they function in encoding, transmitting and expressing genetic information...

assays with no laboratory support.

Global Challenges

For the chips to be used in areas with limited resources, many challenges must be overcome. In developed nations, the most highly valued traits for diagnostic tools include speed, sensitivity, and specificity; but in countries where the healthcare infrastructure is less well developed, attributes such ease of use and shelf life must also be considered. The reagents that come with the chip, for example, must be designed so that they remain effective for months even if the chip is not kept in a climate-controlled environment. Chip designers must also keep cost

Cost

In production, research, retail, and accounting, a cost is the value of money that has been used up to produce something, and hence is not available for use anymore. In business, the cost may be one of acquisition, in which case the amount of money expended to acquire it is counted as cost. In this...

, scalability

Scalability

In electronics scalability is the ability of a system, network, or process, to handle growing amount of work in a graceful manner or its ability to be enlarged to accommodate that growth...

, and recyclability in mind as they choose what materials and fabrication techniques to use.

Examples of Global LOC Application

One active area of LOC research involves ways to diagnose and manage HIV

HIV

Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...

infections. Around 40 million people are infected with HIV in the world today, yet only 1.3 million of these people receive anti-retroviral treatment. Around 90% of people with HIV have never been tested for the disease. Measuring the number of CD4+ T lymphocytes in a person’s blood is an accurate way to determine if a person has HIV and to track the progress of an HIV infection. At the moment, flow cytometry

Cytometry

Cytometry is a general name for a group of biological methods used to measure various parameters of cells. Parameters which can be measured by cytometric methods are cell size, the stage of the cell cycle, the DNA content of the cell, the existence or absence of specific proteins on the cell...

is the gold standard for obtaining CD4 counts, but flow cytometry is a complicated technique that is not available in most developing areas because it requires trained technicians and expensive equipment. But recently Professor Aydogan Ozcan has developed a cytometer for just $5.

Journals

Books

(2003) Edwin Oosterbroek & A. van den Berg (eds.): Lab-on-a-Chip: Miniaturized systems for (bio)chemical analysis and synthesis, Elsevier Science, second edition, 402 pages. ISBN 0444511008.
(2004) Geschke, Klank & Telleman, eds.: Microsystem Engineering of Lab-on-a-chip Devices, 1st ed, John Wiley & Sons. ISBN 3-527-30733-8.
(2009)
(2009)
(2010) 220 pages PREVIEW

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