Lab-on-a-chip

Last updated October 30, 2024

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.

History

Microelectromechanical systems chip, sometimes called "lab on a chip" Labonachip20017-300.jpg — 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 microelectromechanical 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 systems to aid in the detection of biological 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. 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]

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 ^[13]

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-based 3D printing^[14] 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).^[15] 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).^[16] 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.^[17]

The development of LOC devices using printed circuit board (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).^[18] 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.^[19] 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. e) PCBs are compatible with wet deposition methods, to allow for the fabrication of sensors using novel nanomaterials (e.g. graphene).^[20]

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^[21]
part quality may be verified automatically^[22]
safer platform for chemical, radioactive or biological studies because of integration of functionality, smaller fluid volumes and stored energies

Disadvantages

The most prominent disadvantages^[23] 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.^[24] 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.^[25] 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.^[25] 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,^[26] particularly through the development of point-of-care testing devices.^[27] 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, e.g. bacteriuria, or viruses, e.g. 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,^[28] miniaturised microbiological culture 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 tests within three minutes.^[29]^[30] 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 treatment. Only 75% of people living with HIV knew their status.^[31] 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.^{[ citation needed ]} 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.^[32] 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.^[21] 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.^[33]

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.^[34]

Related Research Articles

Microfluidics refers to a system that manipulates a small amount of fluids using small channels with sizes ten to hundreds micrometres. It is a multidisciplinary field that involves molecular analysis, molecular biology, and microelectronics. It has practical applications in the design of systems that process low volumes of fluids to achieve multiplexing, automation, and high-throughput screening. Microfluidics emerged in the beginning of the 1980s and is used in the development of inkjet printheads, DNA chips, lab-on-a-chip technology, micro-propulsion, and micro-thermal technologies.

MEMS 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, and MEMS devices generally range in size from 20 micrometres to a millimetre, although components arranged in arrays can be more than 1000 mm². They usually consist of a central unit that processes data and several components that interact with the surroundings.

<span class="mw-page-title-main">Digital microfluidics</span>

Digital microfluidics (DMF) is a platform for lab-on-a-chip systems that is based upon the manipulation of microdroplets. Droplets are dispensed, moved, stored, mixed, reacted, or analyzed on a platform with a set of insulated electrodes. Digital microfluidics can be used together with analytical analysis procedures such as mass spectrometry, colorimetry, electrochemical, and electrochemiluminescense.

<span class="mw-page-title-main">Biochip</span> Substrates performing biochemical reactions

In molecular biology, biochips are engineered substrates that can host large numbers of simultaneous biochemical reactions. One of the goals of biochip technology is to efficiently screen large numbers of biological analytes, with potential applications ranging from disease diagnosis to detection of bioterrorism agents. For example, digital microfluidic biochips are under investigation for applications in biomedical fields. In a digital microfluidic biochip, a group of (adjacent) cells in the microfluidic array can be configured to work as storage, functional operations, as well as for transporting fluid droplets dynamically.

The term total analysis system (TAS) describes a device that combines and automates all necessary steps for the chemical analysis of a sample. Most current total analysis systems are "micro" total analysis systems which utilize the principles of microfluidics.

Microfabrication is the process of fabricating miniature structures of micrometre scales and smaller. Historically, the earliest microfabrication processes were used for integrated circuit fabrication, also known as "semiconductor manufacturing" or "semiconductor device fabrication". In the last two decades, microelectromechanical systems (MEMS), microsystems, micromachines and their subfields have re-used, adapted or extended microfabrication methods. These subfields include microfluidics/lab-on-a-chip, optical MEMS, RF MEMS, PowerMEMS, BioMEMS and their extension into nanoscale. The production of flat-panel displays and solar cells also uses similar techniques.

A lateral flow test (LFT), is an assay also known as a lateral flow device (LFD), lateral flow immunochromatographic assay, or rapid test. It is a simple device intended to detect the presence of a target substance in a liquid sample without the need for specialized and costly equipment. LFTs are widely used in medical diagnostics in the home, at the point of care, and in the laboratory. For instance, the home pregnancy test is an LFT that detects a specific hormone. These tests are simple and economical and generally show results in around five to thirty minutes. Many lab-based applications increase the sensitivity of simple LFTs by employing additional dedicated equipment. Because the target substance is often a biological antigen, many lateral flow tests are rapid antigen tests.

Micropumps are devices that can control and manipulate small fluid volumes. Although any kind of small pump is often referred to as a micropump, a more accurate definition restricts this term to pumps with functional dimensions in the micrometer range. Such pumps are of special interest in microfluidic research, and have become available for industrial product integration in recent years. Their miniaturized overall size, potential cost and improved dosing accuracy compared to existing miniature pumps fuel the growing interest for this innovative kind of pump.

<span class="mw-page-title-main">Bio-MEMS</span>

Bio-MEMS is an abbreviation for biomedical microelectromechanical systems. Bio-MEMS have considerable overlap, and is sometimes considered synonymous, with lab-on-a-chip (LOC) and micro total analysis systems (μTAS). Bio-MEMS is typically more focused on mechanical parts and microfabrication technologies made suitable for biological applications. On the other hand, lab-on-a-chip is concerned with miniaturization and integration of laboratory processes and experiments into single chips. In this definition, lab-on-a-chip devices do not strictly have biological applications, although most do or are amenable to be adapted for biological purposes. Similarly, micro total analysis systems may not have biological applications in mind, and are usually dedicated to chemical analysis. A broad definition for bio-MEMS can be used to refer to the science and technology of operating at the microscale for biological and biomedical applications, which may or may not include any electronic or mechanical functions. The interdisciplinary nature of bio-MEMS combines material sciences, clinical sciences, medicine, surgery, electrical engineering, mechanical engineering, optical engineering, chemical engineering, and biomedical engineering. Some of its major applications include genomics, proteomics, molecular diagnostics, point-of-care diagnostics, tissue engineering, single cell analysis and implantable microdevices.

Nanofluidic circuitry is a nanotechnology aiming for control of fluids in nanometer scale. Due to the effect of an electrical double layer within the fluid channel, the behavior of nanofluid is observed to be significantly different compared with its microfluidic counterparts. Its typical characteristic dimensions fall within the range of 1–100 nm. At least one dimension of the structure is in nanoscopic scale. Phenomena of fluids in nano-scale structure are discovered to be of different properties in electrochemistry and fluid dynamics.

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 nano-size in a single piece of platform, including a compact disk or DVD. This type of micro-fluidic biochip is based upon the principle of microfluidics to take advantage of non-inertial pumping; for lab-on-a-chip devices using non-inertial valves and switches under centrifugal force and Coriolis effect, this is in order to distribute fluids about the disks in a highly parallel order.

An organ-on-a-chip (OOC) is a multi-channel 3-D microfluidic cell culture, integrated circuit (chip) that simulates the activities, mechanics and physiological response of an entire organ or an organ system. It constitutes the subject matter of significant biomedical engineering research, more precisely in bio-MEMS. The convergence of labs-on-chips (LOCs) and cell biology has permitted the study of human physiology in an organ-specific context. By acting as a more sophisticated in vitro approximation of complex tissues than standard cell culture, they provide the potential as an alternative to animal models for drug development and toxin testing.

Nam-Trung Nguyen is a Vietnamese-Australian researcher in the fields of Microfluidics and Nanofluidics. He is notable for his work on nerve agent detector, PCR, Micromixer, Droplet-based Microfluidics, Micro Magnetofluidics, Liquid Marbles and Micro Elastofluidics. He is currently a Professor and Director of Queensland Micro and Nanotechnology Centre at Griffith University. He was a former Associate Professor at Nanyang Technological University, Singapore. Nguyen is a Fellow of ASME and a Senior Member of IEEE.

An off-stoichiometry thiol-ene polymer is a polymer platform comprising off-stoichiometry thiol-enes (OSTE) and off-stoichiometry thiol-ene-epoxies (OSTE+).

<span class="mw-page-title-main">Bio-FET</span> Type of field-effect transistor

A field-effect transistor-based biosensor, also known as a biosensor field-effect transistor, field-effect biosensor (FEB), or biosensor MOSFET, is a field-effect transistor that is gated by changes in the surface potential induced by the binding of molecules. When charged molecules, such as biomolecules, bind to the FET gate, which is usually a dielectric material, they can change the charge distribution of the underlying semiconductor material resulting in a change in conductance of the FET channel. A Bio-FET consists of two main compartments: one is the biological recognition element and the other is the field-effect transistor. The BioFET structure is largely based on the ion-sensitive field-effect transistor (ISFET), a type of metal–oxide–semiconductor field-effect transistor (MOSFET) where the metal gate is replaced by an ion-sensitive membrane, electrolyte solution, and reference electrode.

Droplet-based microfluidics manipulate discrete volumes of fluids in immiscible phases with low Reynolds number and laminar flow regimes. Interest in droplet-based microfluidics systems has been growing substantially in past decades. Microdroplets offer the feasibility of handling miniature volumes of fluids conveniently, provide better mixing, encapsulation, sorting, sensing and are suitable for high throughput experiments. Two immiscible phases used for the droplet based systems are referred to as the continuous phase and dispersed phase.

Paper-based microfluidics are microfluidic devices that consist of a series of hydrophilic cellulose or nitrocellulose fibers that transport fluid from an inlet through the porous medium to a desired outlet or region of the device, by means of capillary action. This technology builds on the conventional lateral flow test which is capable of detecting many infectious agents and chemical contaminants. The main advantage of this is that it is largely a passively controlled device unlike more complex microfluidic devices. Development of paper-based microfluidic devices began in the early 21st century to meet a need for inexpensive and portable medical diagnostic systems.

Microfluidics refers to the flow of fluid in channels or networks with at least one dimension on the micron scale. In open microfluidics, also referred to as open surface microfluidics or open-space microfluidics, at least one boundary confining the fluid flow of a system is removed, exposing the fluid to air or another interface such as a second fluid.

Jonathan Cooper is Professor of Engineering in the College of Science & Engineering at the University of Glasgow. Professor Cooper has held the Wolfson Chair in Bioengineering at the school since 2009.

Z. Hugh Fan is a US-based biomedical engineer, chemist, scientist, inventor, and academic. Hugh Fan is the Steve and Louise Scott Excellence Fellow and Distinguished Professor of Mechanical and Aerospace Engineering at the University of Florida (UF). At UF, he is Director of the Microfluidics and BioMEMS Laboratory, a research lab and part of the Interdisciplinary Microsystems Group (IMG). Hugh Fan is a Fellow of the American Institute for Medical and Biological Engineering (AIMBE), the American Society of Mechanical Engineers (ASME), and the American Association for the Advancement of Science (AAAS). He is known for his pioneering work in microfluidics in the early 1990s, while his research work spans microfluidics, biomedical microelectromechanical systems (BioMEMS), sensors, cancer and medical diagnostics, and pathogen and virus detection. Hugh Fan's work has significantly contributed to the development of lab-on-a-chip technologies and microfluidic devices for various biomedical applications. He has developed microfluidic devices using aptamers, special DNA or RNA sequences, to isolate and study different types of circulating tumor cells (CTCs) in the blood, offering an alternative to antibody-based methods. In 2018, Hugh Fan and John Lednicky co-led a team at the University of Florida that developed a rapid, cost-effective point-of-care test for the Zika virus. Their work with C. Y. Wu on SARS-CoV-2 in 2020 helped change the opinion on virus transmission route from “droplets” in 2020 to “airborne” in 2021.

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