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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. Laboratories are found in a variety of settings such as schools ...
functions on a single
integrated circuit An integrated circuit (IC), also known as a microchip or simply chip, is a set of electronic circuits, consisting of various electronic components (such as transistors, resistors, and capacitors) and their interconnections. These components a ...
(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 discovery especially used in drug discovery and relevant to the fields of biology, materials science and chemistry. Using robotics, data processing/control software, liquid handling device ...
. LOCs can handle extremely small fluid volumes down to less than
pico- A metric prefix is a unit prefix that precedes a basic unit of measure to indicate a multiple or submultiple of the unit. All metric prefixes used today are decadic. Each prefix has a unique symbol that is prepended to any unit symbol. The pre ...
liters. Lab-on-a-chip devices are a subset of
microelectromechanical systems MEMS (micro-electromechanical systems) is the technology of microscopic devices incorporating both electronic and moving parts. MEMS are made up of components between 1 and 100 micrometres in size (i.e., 0.001 to 0.1 mm), and MEMS devices ...
(MEMS) devices and sometimes called "micro total analysis systems" (μTAS). LOCs may use
microfluidics Microfluidics refers to a system that manipulates a small amount of fluids (10−9 to 10−18 liters) using small channels with sizes of ten to hundreds of micrometres. It is a multidisciplinary field that involves molecular analysis, molecular bi ...
, 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.


History

After the invention of microtechnology (≈1954) for realizing integrated
semiconductor A semiconductor is a material with electrical conductivity between that of a conductor and an insulator. Its conductivity can be modified by adding impurities (" doping") to its crystal structure. When two regions with different doping level ...
structures for microelectronic chips, these
lithography Lithography () is a planographic method of printing originally based on the miscibility, 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 ...
-based technologies were soon applied in pressure sensor manufacturing (1966) as well. Due to further development of these usually
CMOS Complementary metal–oxide–semiconductor (CMOS, pronounced "sea-moss ", , ) is a type of MOSFET, metal–oxide–semiconductor field-effect transistor (MOSFET) semiconductor device fabrication, fabrication process that uses complementary an ...
-compatibility limited processes, a tool box became available to create micrometre or sub-micrometre sized mechanical structures in silicon wafers as well: the
microelectromechanical systems MEMS (micro-electromechanical systems) is the technology of microscopic devices incorporating both electronic and moving parts. MEMS are made up of components between 1 and 100 micrometres in size (i.e., 0.001 to 0.1 mm), and MEMS devices ...
(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, 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 molecular 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, ...
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 electr ...
and DNA microarrays. 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 Adva ...
(Defense Advanced Research Projects Agency), for their interest in portable systems to aid in the detection of
biological Biology is the scientific study of life and living organisms. It is a broad natural science that encompasses a wide range of fields and unifying principles that explain the structure, function, growth, origin, evolution, and distribution of ...
and chemical warfare agents. 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 is the manipulation of matter with at least one dimension sized from 1 to 100 nanometers (nm). At this scale, commonly known as the nanoscale, surface area and quantum mechanical effects become important in describing propertie ...
. 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. The size of the global lab on chip market was estimated at US$5,698 million in 2021 and is projected to increase to US$14,772 million by 2030, at a CAGR of 11.5% from 2022 to 2030


Chip materials and fabrication technologies

The basis for most LOC fabrication processes is
photolithography Photolithography (also known as optical lithography) is a process used in the manufacturing of integrated circuits. It involves using light to transfer a pattern onto a substrate, typically a silicon wafer. The process begins with a photosensiti ...
. Initially most processes were in silicon, as these well-developed technologies were directly derived from
semiconductor A semiconductor is a material with electrical conductivity between that of a conductor and an insulator. Its conductivity can be modified by adding impurities (" doping") to its crystal structure. When two regions with different doping level ...
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, is a silicone polymer with a wide variety of uses, from cosmetics to industrial lubrication and passive daytime radiative cooling. PDMS is particularly known for its ...
(PDMS) processing (e.g.,
soft lithography In technology, soft lithography is a family of techniques for fabricating or Replication (disambiguation), replicating structures using "elastomeric stamps, molds, and conformable photomasks". It is called "soft" because it uses elastomeric mate ...
), Off-stoichiometry thiol-ene polymers (OSTEmer) processing, thick-film- and stereolithography-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. 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 called printed wiring board (PWB), is a Lamination, laminated sandwich structure of electrical conduction, conductive and Insulator (electricity), insulating layers, each with a pattern of traces, planes ...
(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 (LOPCBs). The following are some of the advantages of PCB technology: a) PCB-based circuit design offers great flexibility and can be tailored to specific demands. b) PCB technology enables the integration of electronic and sensing modules on the same platform, reducing device size while maintaining accuracy of detection. c) The standardized and established PCB manufacturing process allows for cost-effective large-scale production of PCB-based detection devices. d) The growth of flexible PCB technology has driven the development of wearable detection devices. As a result, over the past decade, there have been numerous reports on the application of Lab-on-PCB to various biomedical fields, including the fastest SARS-CoV-2 molecular diagnostic test. e) PCBs are compatible with wet deposition methods, to allow for the fabrication of sensors using novel nanomaterials (e.g. graphene).


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
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 ...
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. * 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 noise power, often expressed in deci ...
s.


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 populations in a 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". Problems th ...
, particularly through the development of point-of-care testing devices. In countries with few healthcare resources,
infectious diseases 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 dise ...
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 microorganism, microbial organisms by letting them reproduce in predetermined culture medium under controlled laboratory conditions. Microbial cultures are foundational a ...
assays, immunoassays and
nucleic acid Nucleic acids are large biomolecules that are crucial in all cells and viruses. They are composed of nucleotides, which are the monomer components: a pentose, 5-carbon sugar, a phosphate group and a nitrogenous base. The two main classes of nuclei ...
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 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 controlled environment. Chip designers must also keep
cost 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 of acquisition, in which case the amount of money expended to acquire it i ...
,
scalability Scalability is the property of a system to handle a growing amount of work. One definition for software systems specifies that this may be done by adding resources to the system. In an economic context, a scalable business model implies that ...
, and recyclability 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
infectious diseases 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 dise ...
caused by
bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...
, e.g.
bacteriuria Bacteriuria is the presence of bacteria in urine. Bacteriuria accompanied by symptoms is a urinary tract infection while that without is known as asymptomatic bacteriuria. Diagnosis is by urinalysis or urine culture. ''Escherichia coli'' is the ...
, or
virus A virus is a 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 archaea. Viruses are ...
es, e.g.
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 sympto ...
. A gold standard for diagnosing
bacteriuria Bacteriuria is the presence of bacteria in urine. Bacteriuria accompanied by symptoms is a urinary tract infection while that without is known as asymptomatic bacteriuria. Diagnosis is by urinalysis or urine culture. ''Escherichia coli'' is the ...
( urinary tract infections) is microbial culture. A recent study based on lab-on-a-chip technology, Digital Dipstick, miniaturised
microbiological culture A microbiological culture, or microbial culture, is a method of multiplying microorganism, microbial organisms by letting them reproduce in predetermined culture medium under controlled laboratory conditions. Microbial cultures are foundational a ...
into a dipstick format and enabled it to be used at the point-of-care. Lab-on-a-chip technology can also be useful for the diagnosis and management of viral infections. In 2023, researchers developed a working prototype of an RT-LAMP lab-on-a-chip system called LoCKAmp, which provided results for
SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19, the respiratory illness responsible for the COVID-19 pandemic. The virus previously had the Novel coronavirus, provisional nam ...
tests within three minutes. Managing HIV infections is another area where lab-on-a-chips may be useful. Around 36.9 million people are infected with HIV in the world today, and 59% of these people receive
anti-retroviral The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of mu ...
treatment. Only 75% of people living with HIV knew their 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 cell (biology), cells. Variables that can be measured by cytometric methods include cell size, cell counting, cell count, cell morphology (shape and structure), cell cycle phase, DNA c ...
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 plant from the mustard family (Brassicaceae), native to Eurasia and Africa. Commonly found along the shoulders of roads and in disturbed land, it is generally ...
''. Specifically, plant on a chip is a miniaturized device in which pollen tissues and ovules could be incubated for plant sciences studies.


See also

* Biochemical assays * Dielectrophoresis: detection of cancer cells and bacteria. *
Immunoassay 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 immunoassay ...
: detect bacteria, viruses and cancers based on antigen-antibody reactions. * Ion channel screening (patch clamp) *
Microfluidics Microfluidics refers to a system that manipulates a small amount of fluids (10−9 to 10−18 liters) using small channels with sizes of ten to hundreds of micrometres. It is a multidisciplinary field that involves molecular analysis, molecular bi ...
* Microphysiometry * Organ-on-a-chip * Real-time PCR: detection of bacteria, viruses and cancers. * Testing the safety and efficacy of new drugs, as with lung on a chip * Total analysis system


References


Further reading

;Books * Geschke, Klank & Telleman, eds.: Microsystem Engineering of Lab-on-a-chip Devices, 1st ed, John Wiley & Sons. . * * * * (2012) Gareth Jenkins & Colin D Mansfield (eds)
Methods in Molecular Biology – Microfluidic Diagnostics
Humana Press, {{DEFAULTSORT:Lab-On-A-Chip Integrated circuits Laboratory types Nanotechnology Microfluidics Optofluidics