A lab-on-a-chip (LOC) is a device that integrates one or several

laboratory A laboratory (; ; colloquially lab) is a facility that provides controlled conditions in which scientific or technological research, experiments, and measurement may be performed. Laboratory services are provided in a variety of settings: physici ...

functions on a single integrated circuit (commonly called a "chip") of only millimeters to a few square centimeters to achieve automation and

high-throughput screening High-throughput screening (HTS) is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology, materials science and chemistry. Using robotics, data processing/control software, liquid handlin ...

. LOCs can handle extremely small fluid volumes down to less than pico-liters. Lab-on-a-chip devices are a subset of

microelectromechanical systems Microelectromechanical systems (MEMS), also written as micro-electro-mechanical systems (or microelectronic and microelectromechanical systems) and the related micromechatronics and microsystems constitute the technology of microscopic devices, ...

(MEMS) devices and sometimes called "micro total analysis systems" (µTAS). LOCs may use

microfluidics Microfluidics refers to the behavior, precise control, and manipulation of fluids that are geometrically constrained to a small scale (typically sub-millimeter) at which surface forces dominate volumetric forces. It is a multidisciplinary field tha ...

, the physics, manipulation and study of minute amounts of fluids. 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 when it turned out that µTAS technologies were applicable for more than only analysis purposes.

History

After the invention of microtechnology (~1954) for realizing integrated

semiconductor A semiconductor is a material which has an electrical conductivity value falling between that of a conductor, such as copper, and an insulator, such as glass. Its resistivity falls as its temperature rises; metals behave in the opposite way. ...

structures for microelectronic chips, these

lithography Lithography () is a planographic method of printing originally based on the immiscibility of oil and water. The printing is from a stone ( lithographic limestone) or a metal plate with a smooth surface. It was invented in 1796 by the German ...

-based technologies were soon applied in

pressure sensor A pressure sensor is a device for pressure measurement of gases or liquids. Pressure is an expression of the force required to stop a fluid from expanding, and is usually stated in terms of force per unit area. A pressure sensor usually a ...

manufacturing (1966) as well. Due to further development of these usually CMOS-compatibility limited processes, a tool box became available to create micrometre or sub-micrometre sized mechanical structures in silicon wafers as well: the

(MEMS) era 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 Gas chromatography (GC) is a common type of chromatography used in analytical chemistry Analytical chemistry studies and uses instruments and methods to separate, identify, and quantify matter. In practice, separation, identification or qua ...

, developed in 1979 by S.C. Terry at Stanford University. However, only at the end of the 1980s and beginning of the 1990s did the LOC research start 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 additional cleaning and separation steps. A big boost in research and commercial interest came in the mid 1990s, when µTAS technologies turned out to provide interesting tooling for

genomics Genomics is an interdisciplinary field of biology focusing on the structure, function, evolution, mapping, and editing of genomes. A genome is an organism's complete set of DNA, including all of its genes as well as its hierarchical, three-dim ...

applications, like

capillary electrophoresis Capillary electrophoresis (CE) is a family of electrokinetic separation methods performed in submillimeter diameter capillaries and in micro- and nanofluidic channels. Very often, CE refers to capillary zone electrophoresis (CZE), but other elect ...

and

DNA microarrays A DNA microarray (also commonly known as DNA chip or biochip) is a collection of microscopic DNA spots attached to a solid surface. Scientists use DNA microarrays to measure the expression levels of large numbers of genes simultaneously or to ...

. A big boost in research support also came from the military, especially from

DARPA The Defense Advanced Research Projects Agency (DARPA) is a research and development agency of the United States Department of Defense responsible for the development of emerging technologies for use by the military. Originally known as the Ad ...

(Defense Advanced Research Projects Agency), for their interest in portable

biological Biology is the scientific study of life. It is a natural science with a broad scope but has several unifying themes that tie it together as a single, coherent field. For instance, all organisms are made up of cells that process hereditary ...

, and

chemical warfare Chemical warfare (CW) involves using the toxic properties of chemical substances as weapons. This type of warfare is distinct from nuclear warfare, biological warfare and radiological warfare, which together make up CBRN, the military a ...

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 chemical analysis, environmental monitoring, medical diagnostics and cellomics, but also in synthetic chemistry such as 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, also shortened to nanotech, is the use of matter on an atomic, molecular, and supramolecular scale for industrial purposes. The earliest, widespread description of nanotechnology referred to the particular technological goal o ...

. 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, sensing techniques, and bioanalytical applications.

Chip materials and fabrication technologies

The basis for most LOC fabrication processes is

photolithography In integrated circuit manufacturing, photolithography or optical lithography is a general term used for techniques that use light to produce minutely patterned thin films of suitable materials over a substrate, such as a silicon wafer (electroni ...

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

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 Etching is traditionally the process of using strong acid or mordant to cut into the unprotected parts of a metal surface to create a design in intaglio (incised) in the metal. In modern manufacturing, other chemicals may be used on other type ...

, deposition and bonding,

polydimethylsiloxane Polydimethylsiloxane (PDMS), also known as dimethylpolysiloxane or dimethicone, belongs to a group of polymeric organosilicon compounds that are commonly referred to as silicones. PDMS is the most widely used silicon-based organic polymer, as it ...

(PDMS) processing (e.g.,

soft lithography In technology, soft lithography is a family of techniques for fabricating or replicating structures using "elastomeric stamps, molds, and conformable photomasks". It is called "soft" because it uses elastomeric materials, most notably PDMS. ...

), Off-stoichiometry thiol-ene polymers (OSTEmer) processing, thick-film- and

stereolithography Stereolithography (SLA or SL; also known as vat photopolymerisation, optical fabrication, photo-solidification, or resin printing) is a form of 3D printing technology used for creating models, prototypes, patterns, and production parts in a la ...

-based 3D printing as well as fast replication methods via

electroplating Electroplating, also known as electrochemical deposition or electrodeposition, is a process for producing a metal coating on a solid substrate through the redox, reduction of cations of that metal by means of a direct current, direct electric cur ...

injection molding Injection moulding (U.S. spelling: injection molding) is a manufacturing process for producing parts by injecting molten material into a mould, or mold. Injection moulding can be performed with a host of materials mainly including metals (for ...

and

embossing Emboss or Embossing may refer to: Materials The term usually refers to several techniques for creating a raised pattern on a material: *Paper embossing, the raising of paper and other non-metal products using specific tools to accomplish the task ...

. The demand for cheap and easy LOC prototyping resulted in a simple methodology for the fabrication of PDMS microfluidic devices: ESCARGOT (Embedded SCAffold RemovinG Open Technology). This technique allows for the creation of microfluidic channels, in a single block of PDMS, via a dissolvable scaffold (made by e.g.

3D printing 3D printing or additive manufacturing is the construction of a three-dimensional object from a CAD model or a digital 3D model. It can be done in a variety of processes in which material is deposited, joined or solidified under computer ...

). Furthermore, the LOC field more and more exceeds the borders between lithography-based microsystem technology, nanotechnology and precision engineering. Printing is considered as a well-established yet maturing method for rapid prototyping in chip fabrication. The development of LOC devices using

printed circuit board A printed circuit board (PCB; also printed wiring board or PWB) is a medium used in electrical and electronic engineering to connect electronic components to one another in a controlled manner. It takes the form of a laminated sandwich str ...

(PCB) substrates is an interesting alternative due to these differentiating characteristics: commercially available substrates with integrated electronics, sensors and actuators; disposable devices at low cost, and very high potential of commercialization. These devices are known as Lab-on-PCBs (LOPs).

Advantages

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 * part quality may be verified automatically * safer platform for chemical, radioactive or biological studies because of integration of functionality, smaller fluid volumes and stored energies

Disadvantages

The most prominent disadvantages of labs-on-chip are: * The micro-manufacturing process required to make them is complex and labor-intensive, requiring both expensive equipment and specialized personnel. It can be overcome by the recent technology advancement on low-cost

and laser engraving. *The complex fluidic actuation network requires multiple pumps and connectors, where fine control is difficult. It can be overcome by careful simulation, an intrinsic pump, such as air-bag embed chip, or by using a centrifugal force to replace the pumping, i.e.

centrifugal micro-fluidic biochip The centrifugal micro-fluidic biochip or centrifugal micro-fluidic biodisk is a type of lab-on-a-chip technology, also known as lab-on-a-disc, that can be used to integrate processes such as separating, mixing, reaction and detecting molecules of ...

. * Most LOCs are novel proof of concept application that are not yet fully developed for widespread use. More validations are needed before practical employment. * In the microliter scale that LOCs deal with, surface dependent effects like capillary forces, surface roughness or chemical interactions are more dominant. This can sometimes make replicating lab processes in LOCs quite challenging and 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 (SNR or S/N) is a measure used in science and engineering that compares the level of a desired signal to the level of background noise. SNR is defined as the ratio of signal power to the noise power, often expressed in d ...

Global health

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

global health Global health is the health of the populations in the worldwide context; it has been defined as "the area of study, research and practice that places a priority on improving health and achieving equity in health for all people worldwide". Problem ...

, particularly through the development of

point-of-care testing Point-of-care testing (POCT or bedside testing) is defined as medical diagnostic testing at or near the point of care—that is, at the time and place of patient care. This contrasts with the historical pattern in which testing was wholly or most ...

devices. In countries with few healthcare resources,

infectious diseases An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable d ...

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

microbiological culture A microbiological culture, or microbial culture, is a method of multiplying microbial organisms by letting them reproduce in predetermined culture medium under controlled laboratory conditions. Microbial cultures are foundational and basic diag ...

assays An assay is an investigative (analytic) procedure in laboratory medicine, mining, pharmacology, environmental biology and molecular biology for qualitatively assessing or quantitatively measuring the presence, amount, or functional activity of a ...

immunoassays An immunoassay (IA) is a biochemical test that measures the presence or concentration of a macromolecule or a small molecule in a solution through the use of an antibody (usually) or an antigen (sometimes). The molecule detected by the immunoassa ...

and

nucleic acid Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main ...

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 as 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 control Heating, ventilation, and air conditioning (HVAC) is the use of various technologies to control the temperature, humidity, and purity of the air in an enclosed space. Its goal is to provide thermal comfort and acceptable indoor air quality. H ...

led environment. Chip designers must also keep

cost In Production (economics), production, research, retail, and accounting, a cost is the value of money that has been used up to produce something or deliver a service, and hence is not available for use anymore. In business, the cost may be one o ...

scalability Scalability is the property of a system to handle a growing amount of work by adding resources to the system. In an economic context, a scalable business model implies that a company can increase sales given increased resources. For example, a ...

, and

recyclability Recycling is the process of converting waste materials into new materials and objects. The recovery of energy from waste materials is often included in this concept. The recyclability of a material depends on its ability to reacquire the ...

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

Examples of global LOC application

One of the most prominent and well known LOC devices to reach the market is the at home pregnancy test kit, a device that utilizes paper-based microfluidics technology. Another active area of LOC research involves ways to diagnose and manage common

caused by

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...

, eg. bacteriuria or

virus A virus is a wikt:submicroscopic, submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and ...

, eg.

influenza Influenza, commonly known as "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptom ...

. A gold standard for diagnosing bacteriuria (

urinary tract infections A urinary tract infection (UTI) is an infection that affects part of the urinary tract. When it affects the lower urinary tract it is known as a bladder infection (cystitis) and when it affects the upper urinary tract it is known as a kidney ...

) is microbial culture. A recent study based on lab-on-a-chip technology, Digital Dipstick, miniaturised

into a dipstick format and enabled it to be used at the point-of-care. When it comes to viral infections,

HIV The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immu ...

infections are a good example. Around 36.9 million people are infected with HIV in the world today and 59% of these people receive anti-retroviral treatment. Only 75% of people living with HIV knew their HIV status. 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 is the measurement of number and characteristics of cells. Variables that can be measured by cytometric methods include cell size, cell count, cell morphology (shape and structure), cell cycle phase, DNA content, and the existence or a ...

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. Recently such a cytometer was developed for just $5. Another active area of LOC research is for controlled separation and mixing. In such devices it is possible to quickly diagnose and potentially treat diseases. As mentioned above, a big motivation for development of these is that they can potentially be manufactured at very low cost. One more area of research that is being looked into with regards to LOC is with home security. Automated monitoring of volatile organic compounds (VOCs) is a desired functionality for LOC. If this application becomes reliable, these micro-devices could be installed on a global scale and notify homeowners of potentially dangerous compounds.

Plant sciences

Lab-on-a-chip devices could be used to characterize

pollen tube A pollen tube is a tubular structure produced by the male gametophyte of seed plants when it germinates. Pollen tube elongation is an integral stage in the plant life cycle. The pollen tube acts as a conduit to transport the male gamete cells fr ...

guidance in ''

Arabidopsis thaliana ''Arabidopsis thaliana'', the thale cress, mouse-ear cress or arabidopsis, is a small flowering plant native to Eurasia and Africa. ''A. thaliana'' is considered a weed; it is found along the shoulders of roads and in disturbed land. A winter ...

''. Specifically, plant on a chip is a miniaturized device in which pollen tissues and ovules could be incubated for plant sciences studies.