Lab-on-a-chip

A lab-on-a-chip (LOC) is a device that integrates one or several laboratory 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.[1] LOCs can handle extremely small fluid volumes down to less than pico-liters. Lab-on-a-chip devices are a subset of microelectromechanical systems (MEMS) devices and sometimes called "micro total analysis systems" (µTAS). LOCs may use microfluidics, 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.

This article is about the technology. For the journal, see Lab on a Chip (journal).

History
Microelectromechanical systems chip, sometimes called "lab on a chip"

After the invention of microtechnology (~1954) for realizing integrated semiconductor structures for microelectronic chips, these lithography-based technologies were soon applied in pressure sensor 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 micro electro mechanical systems (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.[2][3] 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.[4] 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 applications, like capillary electrophoresis 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. Sub-micrometre and nano-sized channels, DNA labyrinths, single cell detection and analysis,[5] 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,[6][7][8] system properties,[9] sensing techniques,[10] and bioanalytical applications.[11][12]

Chip materials and fabrication technologies

The basis for most LOC fabrication processes is photolithography. Initially most processes were in silicon, as these well-developed technologies were directly derived from 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, polydimethylsiloxane (PDMS) processing (e.g., soft lithography), Off-stoichiometry thiol-ene polymers (OSTEmer) processing, thick-film- and stereolithography as well as fast replication methods via electroplating, injection molding 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).[13] 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).[14] Furthermore, the LOC field more and more exceeds the borders between lithography-based microsystem technology, nanotechnology and precision engineering.

Advantages

LOCs may provide advantages, which are specific to their application. Typical advantages[10] 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[15]
  • part quality may be verified automatically[16]
  • safer platform for chemical, radioactive or biological studies because of integration of functionality, smaller fluid volumes and stored energies

Disadvantages

The most prominent disadvantages[17] 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.[18] It can be overcome by the recent technology advancement on low-cost 3D printing 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.[19] 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.[19] 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 ratios.

Global health

Lab-on-a-chip technology may soon become an important part of efforts to improve global health,[20] particularly through the development of point-of-care testing devices.[21] 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 microbiological culture assays,immunoassays and nucleic acid 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, scalability, 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 caused by bacteria, eg. bacteriuria or virus, eg. influenza. A gold standard for diagnosing bacteriuria (urinary tract infections) is microbial culture. A recent study based on lab-on-a-chip technology, Digital Dipstick,[22] miniaturised microbiological culture into a dipstick format and enabled it to be used at the point-of-care. When it comes to viral infections, HIV 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.[23] 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 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.[24] 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.[15] 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.[25]

Plant sciences

Lab-on-a-chip devices could be used to characterize pollen tube guidance in Arabidopsis thaliana. Specifically, plant on a chip is a miniaturized device in which pollen tissues and ovules could be incubated for plant sciences studies.[26]

See also

References
  1. Volpatti, L. R.; Yetisen, A. K. (Jul 2014). "Commercialization of microfluidic devices". Trends in Biotechnology. 32 (7): 347–350. doi:10.1016/j.tibtech.2014.04.010. PMID 24954000.
  2. James B. Angell; Stephen C. Terry; Phillip W. Barth (April 1983). "Silicon Micromechanical Devices". Scientific American. 248 (4): 44–55. Bibcode:1983SciAm.248d..44A. doi:10.1038/scientificamerican0483-44.
  3. Terry J.H.Jerman (1979). "A Gas Chromatographic Air Analyzer Fabricated on a Silicon Wafer". IEEE Trans. Electron Devices. 26 (12): 1880–1886. Bibcode:1979ITED...26.1880T. doi:10.1109/T-ED.1979.19791. S2CID 21971431.
  4. A.Manz, N.Graber and H.M.Widmer: Miniaturized total Chemical Analysis systems: A Novel Concept for Chemical Sensing, Sensors and Actuators, B 1 (1990) 244–248.
  5. Chokkalingam Venkat; Tel Jurjen; Wimmers Florian; Liu Xin; Semenov Sergey; Thiele Julian; Figdor Carl G.; Huck Wilhelm T.S. (2013). "Probing cellular heterogeneity in cytokine-secreting immune cells using droplet-based microfluidics". Lab on a Chip. 13 (24): 4740–4744. doi:10.1039/C3LC50945A. PMID 24185478.
  6. Kirby, B.J. (2010). Micro- and Nanoscale Fluid Mechanics: Transport in Microfluidic Devices. Cambridge University Press. ISBN 978-0-521-11903-0.
  7. Bruus, H. (2007). Theoretical Microfluidics.
  8. Karniadakis, G.M.; Beskok, A.; Aluru, N. (2005). Microflows and Nanoflows. Springer Verlag.
  9. Tabeling, P. Introduction to Microfluidic.
  10. Ghallab, Y.; Badawy, W. (2004-01-01). "Sensing methods for dielectrophoresis phenomenon: from bulky instruments to lab-on-a-chip". IEEE Circuits and Systems Magazine. 4 (3): 5–15. doi:10.1109/MCAS.2004.1337805. ISSN 1531-636X. S2CID 6178424.
  11. Berthier, J.; Silberzan, P. Microfluidics for Biotechnology.
  12. Gomez, F.A. Biological Applications of Microfluidics.
  13. Saggiomo, V.; Velders, H. A. (Jul 2015). "Simple 3D Printed Scaffold-Removal Method for the Fabrication of Intricate Microfluidic Devices". Advanced Science. 2 (8): X. doi:10.1002/advs.201500125. PMC 5115388. PMID 27709002.
  14. Vittorio Saggiomo (17 July 2015). "Simple fabrication of complex microfluidic devices (ESCARGOT)" – via YouTube.
  15. Pawell Ryan S (2013). "Manufacturing and wetting low-cost microfluidic cell separation devices". Biomicrofluidics. 7 (5): 056501. doi:10.1063/1.4821315. PMC 3785532. PMID 24404077.
  16. Pawell, Ryan S.; Taylor, Robert A.; Morris, Kevin V.; Barber, Tracie J. (2015). "Automating microfluidic part verification". Microfluidics and Nanofluidics. 18 (4): 657–665. doi:10.1007/s10404-014-1464-1. S2CID 96793921.
  17. Engel, U; Eckstein, R (2002-09-09). "Microforming – from basic research to its realization". Journal of Materials Processing Technology. 125 (Supplement C): 35–44. doi:10.1016/S0924-0136(02)00415-6.
  18. Sanchez-Salmeron, A. J.; Lopez-Tarazon, R.; Guzman-Diana, R.; Ricolfe-Viala, C. (2005-08-30). "Recent development in micro-handling systems for micro-manufacturing". Journal of Materials Processing Technology. 2005 International Forum on the Advances in Materials Processing Technology. 167 (2): 499–507. doi:10.1016/j.jmatprotec.2005.06.027.
  19. Microfluidics and BioMEMS Applications. Microsystems. 10. SpringerLink. 2002. doi:10.1007/978-1-4757-3534-5. ISBN 978-1-4419-5316-2.
  20. Paul Yager; Thayne Edwards; Elain Fu; Kristen Helton; Kjell Nelson; Milton R. Tam; Bernhard H. Weigl (July 2006). "Microfluidic diagnostic technologies for global public health". Nature. 442 (7101): 412–418. Bibcode:2006Natur.442..412Y. doi:10.1038/nature05064. PMID 16871209. S2CID 4429504.
  21. Yetisen A. K. (2013). "Paper-based microfluidic point-of-care diagnostic devices". Lab on a Chip. 13 (12): 2210–2251. doi:10.1039/C3LC50169H. PMID 23652632. S2CID 17745196.
  22. Iseri, Emre; Biggel, Michael; Goossens, Herman; Moons, Pieter; van der Wijngaart, Wouter (2020). "Digital dipstick: miniaturized bacteria detection and digital quantification for the point-of-care". Lab on a Chip. 20 (23): 4349–4356. doi:10.1039/D0LC00793E. ISSN 1473-0197. PMID 33169747.
  23. "Global HIV & AIDS statistics — 2019 fact sheet".
  24. Ozcan, Aydogan. "Diagnosis in the palm of your hand". Multimedia::Cytometer. The Daily Bruin. Retrieved 26 January 2015.
  25. Akbar, Muhammad; Restaino, Michael; Agah, Masoud (2015). "Chip-scale gas chromatography: From injection through detection". Microsystems & Nanoengineering. 1. doi:10.1038/micronano.2015.39.
  26. AK Yetisen; L Jiang; J R Cooper; Y Qin; R Palanivelu; Y Zohar (May 2011). "A microsystem-based assay for studying pollen tube guidance in plant reproduction". J. Micromech. Microeng. 25 (5): 054018. Bibcode:2011JMiMi..21e4018Y. doi:10.1088/0960-1317/21/5/054018.

Further reading
Books
  • Geschke, Klank & Telleman, eds.: Microsystem Engineering of Lab-on-a-chip Devices, 1st ed, John Wiley & Sons. ISBN 3-527-30733-8.
  • Herold, KE; Rasooly, A, eds. (2009). Lab-on-a-Chip Technology: Fabrication and Microfluidics. Caister Academic Press. ISBN 978-1-904455-46-2.
  • Herold, KE; Rasooly, A, eds. (2009). Lab-on-a-Chip Technology: Biomolecular Separation and Analysis. Caister Academic Press. ISBN 978-1-904455-47-9.
  • Yehya H. Ghallab; Wael Badawy (2010). Lab-on-a-chip: Techniques, Circuits, and Biomedical Applications. Artech House. p. 220. ISBN 978-1-59693-418-4.
  • (2012) Gareth Jenkins & Colin D Mansfield (eds): Methods in Molecular Biology – Microfluidic Diagnostics, Humana Press, ISBN 978-1-62703-133-2
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