About 20 years ago, researchers introduced the concept of lab-on-a-chip and envisioned its use as a revolutionary diagnostic tool. So what is a lab-on-a-chip device? What are its main applications, advantages, and downsides? And to what extent is it a promising diagnostic tool? We answer all these questions in the following review.
A lab-on-a-chip is a miniaturized device that offers the solution of conducting multiple-sample biological and biochemical analyses in a single platform. Research on lab-on-a-chip focuses on several applications, including human diagnostics, DNA analysis, and, to a lesser extent, chemical synthesis. Thus, lab-on-a-chip emerges as a promising diagnostic tool as the miniaturization of biochemical operations reduces costs, parallelizes operations, and increases diagnostic speed, sensitivity, and accuracy.
This article provides a general overview of lab-on-a-chip applications, chip manufacturing, advantages, limitations, and future perspectives as a promising diagnostic tool. We will first have a look at the origins of lab-on-a-chip technology. For a more in-depth comprehension of the principles of microfluidics and lab-on-a-chip, we recommend reading the excellent review by P Abgrall and A-M Gue [1] or the one by Temiz et al. [2].
The history of lab-on-a-chip is intrinsically linked to the history of microfluidics.
The origin of microfluidics began in the same manner as microelectronics. In the early 50s, researchers adapted the photolithography process, using light, to fabricate finer detailed micro-sized transistors in silicon. In 1964, researchers demonstrated the first integrated circuit by manufacturing resistors, capacitors, and transistors on the same piece of semiconductor material. Soon, a wide range of sensors and transducers based on photolithography techniques in silicon were developed [3].
Using these manufacturing techniques, the first real lab-on-a-chip was created in 1979 at Stanford University for gas chromatography. Still, lab-on-a-chip research only began in the late 80s with the development of microfluidics and the adaptation of microfabrication processes for producing polymer chips, known as soft-lithography.
In the 90s, researchers began to further explore microfluidics and tried to miniaturize biochemical operations. Early lab-on-a-chip research also focused on cell biology. This is not surprising when considering that microchannels were the same scale size as cells, allowing scientists to easily perform operations at the single-cell level for the first time. Eventually, researchers began to integrate all the required steps from sample collection to final analysis onto the same chip, known as the micro total analysis system (µTAS), showing the real potential of lab-on-a-chip technologies.
Nowadays, it is possible to fabricate fully customized lab-on-a-chip devices in any lab without a clean room, thanks to available standalone lab-on-a-chip fabrication stations.
Microfluidics is both the science and application that manipulate picoliters of fluids and manufacture microminiaturized devices and is the core technology behind lab-on-a-chip. It can integrate millions of microchannels, each measuring mere micrometers, on a single chip that fits in your hand. This process enables the efficient handling of small volumes of fluids (e.g., reagents for biochemical reactions).
Lab-on-a-chip is a microfluidic platform that integrates various laboratory operations such as biochemical analysis, chemical synthesis, or DNA sequencing. Thus, lab-on-a-chip devices are not just a collection of microchannels, complete lab-on-a-chip diagnostic systems require integrated pumps, electrodes, valves, electrical fields, and electronics. Nowadays, various flow control instruments can be used to create a full lab-on-a-chip system.
Lab-on-a-chip not only shows the capacity for integration and parallelization but also demonstrates superior performance compared to conventional technologies. This is true for the different lab-on-a-chip applications discussed below.
Extensive research has been conducted on lab-on-a-chip. Here are some examples of applications where lab-on-a-chip shows great promise.
Molecular analysis is one of the first fields to receive the attention of microfluidic technology. Lab-on-a-chip offers high benefits in terms of DNA/RNA amplification and detection while keeping the same sensitivity. The integration of PCR onto a lab-on-a-chip, called micro PCR, allows ten times faster DNA amplification, due to the high-speed thermal shifts. ELVESYS developed the world’s fastest qPCR system-FASTGENE.
Lab-on-a-chip provides a whole new world of opportunities for DNA & RNA sequencing. The first human genome projects took years and required the work of hundreds of researchers. Today, by integrating an array of DNA probes into lab-on-a-chip, we can sequence genomes thousands of times faster. Moreover, nanopore technologies, which still need to be optimized, hold great potential in the future for being much faster for genome sequencing. Platforms are being developed for testing long and short-fragment gene deletions, single-base substitutions and insertions (single nucleotide polymorphism), and pathogen-specific DNA sequences.
Biomolecular operations done in lab-on-a-chip show great potential for ultra-fast bacteria and virus detection, but also for disease biomarker identification. Additionally, lab-on-a-chip solutions hold enormous possibilities for immunoassays, which can be done in tens of seconds instead of minutes.
Recently, CRISPR/Cas technology has been integrated into lab-on-a-chip devices and revealed a potential as next-generation diagnostic tools. For instance, CRISPR/Cas13a-based amplification method integrated into a mobile phone microscopy on a PDMS chip was able to detect as low as 100 copies per μL of SARS-CoV-2 RNA in 30 min [4]. Electronic microfluidic devices combined with CRISPR/Cas benefit from specific cleavage and ingenious electrochemical signal outputs to achieve ultrasensitive detection of infectious diseases [5].
In the field of proteomics, lab-on-a-chip provides the opportunity to perform protein analysis while integrating all the steps within the same chip: extraction from the cell, separation by electrophoresis, digestion, and analysis using mass spectrometry. These integrated processes show the ability to greatly shorten protein analysis from hours, with a macroscopic system, to a few minutes with lab-on-a-chip devices.
Lab-on-a-chip also shows great potential for protein crystallization, an important research field that reveals the 3D structure of a protein. Researchers can control simultaneously and in the fastest way possible all the parameters enabling the crystallization of a given protein. It is then possible to greatly parallelize crystallization experiments to speed up the identification of appropriate conditions for unknown proteins and study their structures using X-ray diffraction.
Since microchannels are the same typical size as cells, lab-on-a-chip research soon turned to cell biology for high-throughput screening of single cells. This represents a mini cell culture system with cells being exposed to controlled flow rates and experimental conditions. Lab-on-a-chip demonstrates the ability to control cells at the single-cell level while dealing with a large number of cells in seconds. It requires fewer cell media components and fewer cells than conventional cell culture, which is beneficial if working with a precious cell population. It is possible to apply different personalized microenvironments on the separated cells via multiple chambers, to analyze thousands of different conditions or replicates. Potentially, the flow rate can switch quickly in just tens of milliseconds, exposing the cells to gradients of different compounds, which is interesting for studying cell migration and chemotaxis [6].
There are several other applications for lab-on-a-chip in cell biology, including micro patch clamp, control of stem cell differentiation, high-speed flow cytometry, sperm sorting, and, more generally, cell sorting.
The ability to perform fast heating and cooling at the microscale allows for higher efficiency in some chemical reactions. Therefore, much research has been conducted using lab-on-a-chip as micro-sized and highly parallelized microchemical reactors. Lab-on-a-chip devices minimize safety risks when dealing with dangerous and explosive compounds due to the usage of small volumes at a time.
In the following section, we will have a look at the different manufacturing materials for lab-on-a-chip.
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Lab-on-a-chip uses the most common microfluidic device manufacturing technologies and depending on their applications, various polymers. Such technologies enable the integration of microchannels with micrometer-scale sizes.
Silicon: The first lab-on-a-chip was made of silicon, and it seems like a normal choice since microtechnologies are based on the microfabrication of silicon chips. Silicon was first selected due to its resistance to organic solvents, simplicity of use in metal deposition, and high thermo-conductivity. However, silicon was soon replaced by glass then polymers, mainly because it is expensive, not optically transparent (except for IR), and requires a clean room and a strong knowledge of microfabrication. Moreover, the electrical conductivity of silicon makes it impossible to use for lab-on-a-chip operations requiring high voltage (like electrophoresis) [7].
Even if silicon seems like an obsolete candidate, it is still a relevant choice for the industrialization of some demanding lab-on-a-chip applications and is still used in research labs [8]. This assumption considers the high precision of silicon microfabrication, the maturity of the process, the investments put into the silicon industry, and the ability to integrate any kind of microelectrode and even electronics on the same chip.
Glass: Glass is optically transparent, chemically inert, compatible with biological samples, and has low non-specific adsorption. Thus, glass is a very good candidate for the industrialization of diverse lab-on-a-chip applications. However, the fabrication of glass lab-on-a-chip requires clean rooms and researchers with a strong knowledge of microfabrication. Thus, glass lab-on-a-chip is not a good candidate for research labs [9].
PDMS: PDMS (polydimethylsiloxane) is a transparent and flexible elastomer, cheap and easy to use for the microfabrication of lab-on-a-chip by casting. Moreover, lab-on-a-chip made of PDMS has the advantage of the easy integration of quake microvalves for fast flow switch and air permeability for cell culture studies. Widely used for lab-on-a-chip prototyping in research labs, PDMS shows severe limitations for industrial production. Because the material is subject to ageing, and because it tends to absorb hydrophobic molecules, it is hard to integrate electrodes into a PDMS chip [10]. Finally, PDMS is not compatible with high-throughput chip fabrication processes such as hot embossing or injection molding.
Thermopolymers (PMMA, PS): Thermoplastic polymers are widely used by researchers to fabricate lab-on-a-chip devices. Even if it is a little bit trickier and more expensive to implement than PDMS, thermoplastics are good candidates for the fabrication of lab-on-a-chip since they are transparent, compatible with micrometer-sized lithography, and are more chemically inert than PDMS. The thermoplastic material can be chosen according to its mechanical, thermal, chemical, and optical properties [10]. Thermoplastic materials can be good candidates for the industrialization of some lab-on-a-chip, as proven by some studies [11].
Paper: Supported by G. Whiteside, one of the most famous microfluidic researchers, lab-on-a-chip devices based on paper technologies have strong outcomes for applications requiring ultra-low costs. This technology can open up the field of diagnostics and make it accessible to lower-income and limited-resource populations (Picture from Wyss Institute). More and more studies focus on developing novel paper-based lab-on-a-chip platforms [8, 12]. For instance, a paper-based lab-on-a-chip device coupled with immunoassay can detect clinically significant levels of metabolites of interest in urine samples [13].
Digital microfluidics: Digital microfluidic is a platform for lab-on-a-chip systems based on arrays of microelectrodes for the precise design, composition, and manipulation of discrete droplets and/or bubbles. It aims to create fluid-fluid dispersion inside micro-channels. Digital microfluidic allows precise manipulation capability and a tiny reaction space in the order of picoliters to microliters, thus increasing biomolecule concentration and limiting exogenous contaminations. Due to these advantages, digital microfluidic was proven efficient for nucleic acids, proteins, and hormones analysis, based cell assays, and pathogenic bacterial detection [14].
As we have briefly seen, the use of lab-on-a-chip has many advantages compared to conventional technologies, these points are detailed below.
High parallelization and diagnosis: Lab-on-a-chip technology will allow hundreds of analyses to be performed simultaneously on the same chip, due to integrated microchannels. This will allow medical doctors to target specific illnesses during the consultation to quickly and effectively prescribe the best-suited antibiotic or antiviral.
Ease of use: Analyses comparable to those conducted in full analytical laboratories can be done in a chip that fits your hand.
Less human error: Since it will strongly reduce human handling, automatic diagnoses done using lab-on-a-chip will greatly reduce the risk of human error.
Fast response time: At the micrometric scale, the flow switch, and diffusion of chemicals and heat are faster. One can change, for example, the temperature in hundreds of ms, which enables faster DNA amplification.
Low-volume samples: Lab-on-a-chip systems only require a small amount of reagents for each analysis. Thus, it is possible to detect many illnesses without requiring large quantities of blood from patients.
High sensitivity: Thanks to fast reactivity at the microscale, one can control in real-time the environment of a chemical reaction, leading to more controlled results.
Portability: Due to their automation, and low energy consumption, lab-on-a-chip devices can be used in outdoor environments for air and water monitoring without the need for human intervention.
Low cost and high accessibility: As numerous tests are performed on the same chip, the cost of each analysis is reduced to a negligible price. In addition, lab-on-a-chip will reduce the need for trained medical staff, and the cost of infrastructure. As a result, lab-on-a-chip technology will make modern medicine more accessible to developing countries at reasonable costs [15].
In one sentence: We can expect lab-on-a-chip to save numerous lives.
As for every technology, the use of lab-on-a-chip is dealing with some limitations worth mentioning. In parallel, research is ongoing to encounter these challenges.
Industrialization: Most lab-on-a-chip technologies are not yet ready for industrialization. We are not quite sure which fabrication technologies will become the standard for ultra-multiplex diagnosis.
Signal/noise ratio: For some applications, miniaturization increases the signal/noise ratio and as a result, lab-on-a-chip provides poorer results than conventional techniques.
Ethics and human behavior: The DNA sequencing potential of lab-on-a-chip may enable anyone to sequence DNA using a drop of saliva. Without regulations, the widespread accessibility of lab-on-a-chip may generate fears about its use as a diagnostic tool by the untrained public at home.
Need for an external system to work: Even if lab-on-a-chip devices are small and powerful, they require specific machinery such as electronics or flow control systems to work properly. External devices increase the final size and cost of the overall system, and some flow control equipment can often cause limitations for lab-on-a-chip performance. We have a complete brand of high-precision flow control systems for lab-on-a-chip.
It would take a long time to describe all the currently ongoing research on lab-on-a-chip. It’s enough to say that contemporary research on lab-on-a-chip technology focuses on three main aspects:
Much research is being conducted on increasing the ease of lab-on-a-chip use. Here are cited a few interesting studies working on lab-on-a-chip integrating smartphones [16, 17] for cholesterol testing [18], anemia diagnosis [19], cardiovascular diseases monitoring [20], or Elisa assays [21].
There is also much research being done to improve current technologies for given applications including cell separation [22], DNA sequencing through nanopores [23], micro qPCR, and microreactors. Micro PCR remains one of the most promising technologies for future high-throughput diagnostics. Ongoing research focuses mainly on high parallelization by multiplying PCR chambers, digital microfluidics to perform PCR in micro-droplets, and the latest advances in molecular biology to perform simultaneous PCR in the same mix. Research also strongly focuses on enabling lower detection levels and increasing PCR efficiency while reducing false positives and negatives.
Since the impact of these technologies on our daily lives is now evident, governments and companies are investing more and more in the research and production of lab-on-a-chip devices. We expect that lab-on-a-chip technologies will be able to provide real-time monitoring of health at home, and will be widely used in hospital departments and eventually in the practitioner’s office.
Lab-on-a-chip’s dream is to integrate into a single chip thousands of biochemical operations, using a single drop of blood from the patient to precisely diagnose potential diseases. As we have seen, we are currently quite far from this, but lab-on-a-chip devices are already commercialized for several single tests, such as HIV [24] or glucose detection [25]. Point-of-care platforms are being developed for DNA testing to detect bacterial urinary tract infections and gene mutations related to thalassemia [26].
In the coming years, lab-on-a-chip devices will certainly change our way of practicing medicine. These devices promise to enhance medical care quality due to their ability to perform a complete patient diagnosis during the consultation and at the patient’s bedside. Moreover, lab-on-a-chip diagnosis does not require well-trained staff or advanced infrastructure. Thus, qualified doctors can focus only on prescribing treatment. The real-time diagnosis quickly providing laboratory evidence will increase the chances of survival for patients in emergency services and allow the appropriate treatment to be given to each patient.
A complete diagnosis will greatly reduce antibiotic resistance, which is currently one of the biggest challenges of the decade. Moreover, the ongoing development of highly sensitive biosensors to detect biomolecules of interest is essential for diagnosing a wide range of diseases. The ability to perform diagnosis at a low cost will allow the detection and treatment of illnesses at an earlier stage. Lab-on-a-chip will offer developing countries’ populations access to diagnosis and appropriate treatment without the use of rare and costly medications [27].
Looking at recent research and products entering the market, we now can be sure that lab-on-a-chip will further change the way we do diagnostics. There is an increasing demand for lab-on-a-chip testing in clinical diagnosis and several devices have been commercialized for key applications such as glucose monitoring, HIV detection, or heart attack diagnostics.
The challenge for industrial research will be to incorporate on the same lab-on-a-chip the maximum number of individual operations to decrease costs and increase ergonomics, and diagnosis speed. At the moment, technologies are not unified, and there is no clear decision about the most promising material. The answers will depend on technological potentiality, but also perhaps on economic and industrial points of view regarding a synergy with already installed systems such as silicon micromachining.
For more reviews about microfluidics, you can have a look here: “Microfluidics reviews”. The photos in this article come from the Elveflow® data bank, Wikipedia, or elsewhere if specified. Article written by Guilhem Velvé Casquillas and Timothée Houssin and revised by Lauren Durieux. Updated by Celeste Chidiac in 2023.
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