Introduction to lab-on-a-chip 2015 : review, history and future

Introduction to lab-on-a-chip

Biochip-lab-on-a-chip-LOC-definitionA lab-on-a-chip is a miniaturized device that integrates onto a single chip one or several analyses which are usually done in a laboratory, analyses such as DNA sequencing or biochemical detection. Research on lab-on-a-chip mainly focuses on human diagnostics and DNA analysis. Less often, lab-on-a-chip research focuses on the synthesis of chemicals. Miniaturization of biochemical operations normally handled in a laboratory has numerous advantages such as cost efficiency, parallelization, ergonomy, diagnostic speed and sensitivity. The emergence of the lab-on-a-chip field mainly relies on two core technologies: microfluidics and molecular biology. (Tutorial about microfluidics here)

Microfluidic technologies used in lab-on-a-chip devices enable the fabrication of millions of microchannels, each measuring mere micrometers, on a single chip that fits in the palm of your hand. The microchannels enable the handling of fluids in quantities as low as a few picoliters as well as the manipulation of biochemical reactions at very small volumes. Of course, to enable all of these operations, lab-on-a-chip devices are not just a collection of microchannels. They also require integrated pumps, electrodes, valves, electrical fields and electronics to become complete lab-on-a-chip diagnostic systems. (click here to learn more about Elveflow microfluidic flow control brand)

The basis of the lab-on-a-chip dream is to integrate onto a single chip thousands of biochemical operations that could be done by splitting a single drop of blood collected from the patient in order to get a precise diagnosis of  potential diseases. As we will see, we are quite far from this, but current technologies are ready to enable the development of labs-on-a-chip, bringing us closer to the realization of this dream. In the following decades, lab-on-a-chip advancements will change the way we do diagnostics.

In this tutorial, we will not enter the details of all of the ongoing research on lab-on-a-chip technology, but we will try to give you a general overview of the field and our thoughts about its future role in diagnostics. For more comprehensive information, we recommend you to read the excellent review by P Abgrall and A-M Gue [1],

History of lab-on-a-chip

APOLLO-Program-NASA-History-of-lab-on-a-chipThe history of lab-on-a-chip is intrinsically linked to microfluidics. And microfluidics is intrinsically linked to the history of the microtechnology of semiconductors.

To advance the Apollo program, the United States invested billions of dollars to miniaturize calculators in order to send them into space. In the early 50s researchers adapted photographic technologies to create photolithography in order to fabricate micro-sized transistors and thus, microtechnologies and microfabrication were born. These discoveries led to our last technological revolution, which gave birth to modern information technologies and telecommunications.

Ten years later, in the 60s, researchers used these technologies to fabricate micromechanical structures called MEMS, enabling the production of miniaturized accelerometers for use in daily objects such as airbags and smartphones.

Using these fabrication techniques, the first real lab-on-a-chip was created in 1979 at Stanford University for gas chromatography. However, major lab-on-a-chip research only began in the late 80s with the development of microfluidics and the adaptation of microfabrication processes for the production of polymer chips. This adaptation of microfabrication techniques to polymer took the name of soft-lithography. (Tutorial about soft-lithography here)

Silicon manufacturing used for microelectronics was certainly efficient, but required high investment costs and specialized knowledge. The ability to easily fabricate polymer microchips enabled many research laboratories to start their own investigations into lab-on-a-chip technologies. Today, it is even possible to fabricate fully customized lab-on-a-chip devices in any lab without the need of a clean room (click here to learn more about our standalone lab-on-a-chip fabrication stations).

LOC-lab-on-a-chip-historyThen, in the 90s many researchers began to explore microfluidics and tried to miniaturize biochemical operations such as PCR. Early lab-on-a-chip research also focused on cell biology. This is not surprising when considering that the microchannels were at the same scale size as that of cells. These advances enabled scientists to easily perform for the first time operations at the single cell level. Much research has been done on the miniaturization of genomic biochemical operations such as PCR, electrophoresis, DNA microarray, pretreatment step, cell lysis, etc. Eventually, researchers began to integrate all the required steps from sample collection to final analysis onto the same chip, showing the real potential of lab-on-a-chip technologies. The kind of lab-on-a-chip devices that enable researchers to perform all the operations from sample collection to analysis is generally called the Micro total analysis system (µTAS).

Military agencies such as the DARPA and the DGA were soon interested in lab-on-a-chip technologies since such advancements would enable them to detect as soon as possible biological threats towards troops and civilians. Like 30 years before with semiconductors and space exploration programs, these agencies invested a lot of money in advancing research on lab-on-a-chip.

Today, all the main applications of lab-on-a-chip systems has been investigated. For some applications, lab-on-a-chip not only shows the capacity of integration and parallelization, but also demonstrates superior performance compared to conventional technologies. For example, in the case of PCR (a technology used to multiply DNA for pathogen detection), the integration of PCR onto a lab-on-a-chip allows DNA to be amplified ten times faster than with conventional systems (click here for a tutorial about microPCR).

Lab-on-a-chip: core technologies and applications

Much research has been and is being conducted on lab-on-a-chip. Most of it focuses on diagnostic technologies. We give here some examples of applications where lab-on-a-chip shows great promises.

Lab-on-a-chip and Molecular Biology

LOC-lab-on-a-chip-historyFor DNA/RNA amplification and detection, lab-on-a-chip offers high gains in terms of detection speed while keeping the same sensitivity. Since DNA amplification using PCR relies on thermal cycles, the ability to perform high-speed thermal shifts at the microscale explains why lab-on-a-chip became the fastest way of doing PCR. (ELVESYS developed the world’s fastest qPCR system—if you are interested in knowing more about this technology, discover FASTGENE here).

For DNA & RNA sequencing, lab-on-a-chip provided a whole new world of opportunities. The first human genome projects took years and required the work of hundreds of researchers to sequence the human genome. Today, using lab-on-a-chip to integrate an array of DNA probes, we are able to sequence genomes thousands of times faster. Moreover, nanopore technologies, which still need to be optimized, hold great potential in the future for being far faster for genome sequencing than actual lab-on-a-chip using an array of DNA probes. All the biomolecular operations done in labs-on-a-chip show great potential for ultra fast bacteria and virus detection, but also for disease biomarker identification (DNA and RNA). Additionally, labs-on-a-chip hold enormous possibilities for immunoassays, which can be done in tens of seconds instead of ten minutes as when using macroscopic technologies. In the field of molecular separation too, labs-on-a-chip demonstrate more efficient separation than with conventional systems. (Discover our tutorial about microfluidic DNA analysis here).

Lab-on-a-chip and proteomics

Lab-on-a-chip and proteomicsIn the field of proteomics lab-on-a-chip provides the opportunity to perform protein analyses 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 macroscopic system to a few minutes with lab-on-a-chip. Lab-on-a-chip shows also great potential for protein crystallization (crystallization is an important research field because it reveals the 3D structure of a protein). Using lab-on-a-chip, researchers are able to control simultaneously and in the fastest way possible all the parameters enabling the crystallization of a given protein. The most important factor is the possibility to greatly parallelize crystallization conditions and in order to speed up the discovery of crystallization conditions for unknown proteins and study their structures using X-ray diffraction, for example).

Lab-on-a-chip and Cell Biology

Lab-on-a-chip and Cell BiologySince microchannels are the same typical size as cells, lab-on-a-chip research soon turned its focus on cell biology. Lab-on-a-chip demonstrates the ability to control cells at the single-cell level while dealing with a large amount of cells in seconds. At the microscale level flow switch can be very fast and goes down to just tens of milliseconds (click here to learn more about our microfluidic flow control systems for fast flow switch). Using fast optical detectors (such as the Opto Reader, for example) one can detect and isolate a given cell (such as cancerous cell made fluorescent using antibodies) with high throughput. 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 and cell sorting. (Discover our tutorial about microfluidic for cell biology here).

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Lab-on-a-chip and Chemistry

Lab-on-a-chip and ChemistryThe ability to perform fast heating and cooling at the microscale enables higher efficiency in some chemical reactions. Therefore, much research has been conducted on using labs-on-a-chip as microsized and highly parallelized micro chemical reactors. Lab-on-a-chip devices can also be of interest when dealing with dangerous and explosive compounds in that they contain risks by dealing with smaller volumes at a time.

 

 

Lab-on-a-chip: fabrication technologies

Lab-on-a-chip uses the most common microfluidic device fabrication technologies, and depending on their applications, various polymers. Such technologies enable the integration of microchannels with sizes close to 1 micrometer (for a tutorial about microfluidic fabrication techniques click here).

PDMS lab-on-a-chipPDMS lab-on-a-chip: Research labs often use PDMS for lab-on-a-chip prototyping. PDMS (polydimethylsiloxane) is a transparent and flexible elastomer. PDMS is widely used because it is very easy and cheap to fabricate PDMS labs-on-a-chip by casting (discover tutorial about PDMS casting here). Moreover, labs-on-a-chip made of PDMS take advantage of the easy integration of quake microvalves (tutorial about quake valve here) for fast flow switch and permeability of air for cell culture and studies. Widely used for lab-on-a-chip prototyping, PDMS shows severe limitations for industrial production. Because the material is subject to ageing, and because PDMS absorbs hydrophobic molecules, it is hard to integrate electrodes into a PDMS chip (discover here our tutorial on PDMS and microfluidics).

Thermopolymers lab-on-a-chipThermopolymers (PMMA PS…) lab-on-a-chip: Thermoplastic polymers are widely used by researchers to fabricate labs-on-a-chip. Even if it is a little bit more tricky and expensive to implement than PDMS, thermoplastics are good candidates for the fabrication of labs-on-a-chip since they are transparent, compatible with micrometer-sized lithography and more chemically inert than PDMS. For certain applications, some research teams obtained very good results with thermoplastic labs-on-a-chip, and since it is possible to integrate microelectrodes into them, thermoplastic materials can be good candidates for the industrialization of some labs-on-a-chip.

Glass lab-on-a-chipGlass lab-on-a-chip:  Transparent, compatible with micrometer sized machining, chemically inert, with a wide range of well-known chemical surface treatments and reproducible electrode integration, glass is a very good candidate for the industrialization of labs-on-a-chip. From a research point of view, the fabrication of glass labs-on-a-chip require clean rooms and researchers with a strong knowledge of microfabrication. Thus, glass lab-on-a-chip  are not available to all research labs.

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Silicon lab-on-a-chipSilicon lab-on-a-chip: The first lab-on-a-chip was made in silicon, and it seems like quite a normal choice since microtechnologies are based on the micromachining of silicon. Nowadays researchers do not often use silicon for labs-on-a-chip, mainly because silicon is expensive, not optically transparent (except for IR) and requires a clean room as well as 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). Still, even if nowadays silicon seems like an obsolete candidate for the industrialization of lab-on-a-chip, we believe that taking into account the high precision of silicon machining, the maturity of and the investments put into the silicon micromachining industry, and the ability to integrate any kind of microelectrode and even electronics on the same chip, silicon may still be a relevant choice for the industrialization of some demanding lab-on-a-chip applications.

Paper lab-on-a-chipPaper lab-on-a-chip: lab-on-a-chip devices based on paper technologies may have strong outcomes for applications requiring ultra low-costs. Supported by G Whiteside, one of the most famous microfluidic researchers, paper labs-on-a-chip may find their market in the future. We hope it will as the idea is very seducing and could open up the field of diagnostics and make it accessible to lower-income and limited-resource populations. (Picture from Wyss institute)

 

Advantages of lab-on-a-chip compared to conventional technologies

Low cost: Microtechnologies will decrease the cost of analysis much in the way they decreased the cost of computed calculation. Integration will enable numerous tests to be performed on the same chip, reducing to a negligible price the cost of each individual analysis.

High parallelization: Thanks to its capacity for integrating microchannels, lab-on-a-chip technology will enable tens or hundreds of analyses to be performed simultaneously on the same chip. This will enable doctors to target specific illnesses during the time of a consultation in order to prescribe more quickly and effectively the best-suited antibiotic or antiviral.

Ease of use and compactness: Lab-on-a-chip enables the integration of a large number of operations within a small volume. In the end, a chip of just a few centimeters squared coupled with a machine as small as a computer will enable analyses comparable to those done in full analytical laboratories. Diagnostics using lab-on-a-chip will require a lot less handling and complex operations and in most cases, they will be able to be performed on site by a nurse.

Reduction of 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 compared with classical analytical processes done in laboratories.

Faster response time and diagnosis: At the micrometric scale, diffusion of chemicals, flow switch and diffusion of heat is faster. One can change the temperature in hundreds of ms (which enables, for example, faster DNA amplification using PCR) or the mixing of chemicals by diffusion in seconds (to enable faster biochemical reactions, for example).

Low volume samples: Because lab-on-a-chip systems only require a small amount of blood for each analysis, this technology will decrease the cost of analysis by reducing the use of expensive chemicals. Last but not the least, it will permit the detection of a high number of illnesses without requiring large quantities of blood from patients.

Real time process control and monitoring increase sensitivity: Thanks to fast reactivity at the microscale, one can control in real time the environment of a chemical reaction in the lab-on-a-chip, leading to more controlled results.

Expendable: Due to their low price, automation and low energy consumption, lab-on-a-chip devices will also be able to be used in outdoor environments for air and water monitoring without the need for human intervention.

Share the health with everybody: Lab-on-a-chip will reduce diagnostic costs, the formation of 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. [6]

In one sentence: We can clearly expect lab-on-a-chip to save numerous lives.

Limitations of lab-on-a-chip compared to classic technologies

Industrialization: Most lab-on-a-chip technologies are not yet ready for industrialization. Regarding its core application, the ultra multiplex diagnosis, at this time we are not certain which fabrication technologies will become the standard.

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 behaviour: Without regulations, real time processing and the widespread accessibility of labs-on-a-chip may generate some fears of the untrained public diagnosing potential infections at home. Moreover the DNA sequencing potential of lab-on-a-chip may enable anyone to sequence the DNA of others using a drop of saliva.

lab-on-a-chip-external-systemLab-on-a-chip needs an external system to work: Even if lab-on-a-chip devices can be small and powerful, they require specific machinery such as electronics or flow control systems to be able to work properly. Without a precise system to inject, split and control the positioning of samples, labs-on-a-chip are useless. External devices increase the final size and cost of the overall system and some, particularly flow control equipment, can often pose limitations for lab-on-a-chip performance.  (click here if you want to know more about our brand of high precision flow control systems for lab-on-a-chip)

Lab-on-a-chip: current challenges & research

It would take a long time to describe all the currently on-going lab-on-a-chip research. It’s enough to say that contemporary research on lab-on-a-chip technology focuses on three main aspects:

- The industrialization of lab-on-a-chip technologies to make them ready for commercialization. This includes the adaptation of fabrication processes, the design of specific surface treatments, flow control system … etc… (if you need a partner for your lab on chip industrialization, discover our OEM flow control brand or contact us)

- The increase in the maximum number of biological operations able to be integrated on the same chip and the increase in parallelization to achieve the detection of hundreds of pathogens in the same microfluidic cartridge.

- Fundamental research on certain technologies with a high potential impact, such as DNA reading through nanopore, which requires more investigation in order to be applicable.

Much research is being conducted on increasing the ease of use of lab-on-a-chip. Some examples include  enabling the use of basic lab-on-a-chip functions using a smartphone [2] for cholesterol testing [3], label free bio detection [4] or Elisa assays [5]. ( Figure 2: from[2]: Lab Chip, 2014, 14, 3159 )

Lab-on-a-chip-and-smartphone-research

There is also much research being done to improve current technologies for given applications including cell separation [7], DNA sequencing through nanopore, micro qPCR and micro reactors. In the case of microPCR, which is one of the most promising technologies for future high throughput diagnostics, research focuses mainly in enabling high parallelization by a multiplication of the PCR chamber, the use of digital microfluidics to perform PCR in micro-droplets and uses 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.

Today some labs-on-a-chip are already commercialized for targeted applications such as glucose monitoring or specific pathology detection.  In a near future we can expect that labs-on-a-chip will widely be used in hospitals everywhere and eventually inside the practitioner’s office. Later we can expect that lab-on-a-chip technologies will be able to provide real time monitoring of health at home. This is why governments and companies are investing more and more in labs-on-a-chip since it is now clear that these technologies will change our daily lives.

How lab-on-a-chip can change our vision of medicine

Lab-on-a-chip-and-medicineIn a near future, lab-on-a-chip devices, with their ability to perform complete diagnosis of a patient during the time of a consultation, will change our way of practicing medicine. Diagnosis will be done by people with lower qualifications, thus enabling doctors to focus only on treatment. Real time diagnosis will increase the chances of survival for patients in emergency services and will enable the appropriate treatment to be given to each patient. A complete diagnosis will greatly reduce antibio-resistance, which is currently one of the biggest challenges of the decade. The ability to perform diagnosis at low cost will also routinely change the way we see medicine and then enable us to detect illnesses at an earlier stage and treat them as soon as possible. In developing countries, lab-on-a-chip will enable healthcare providers to open diagnostics to a wider population and to give the appropriate treatment to people who really need it without the use of rare and costly medications.

Lab-on-a-chip: Conclusions and perspectives

lab-on-a-chip-perspectivesLooking at recent researches and products entering the market, we now can be sure that lab-on-a-chip will change the way we do diagnostics in a near future.  Several labs-on-a-chip have been commercialized for some 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 amount of individual operations in order to decrease costs and increase ergonomics as well as the speed of diagnosis. At the moment, technologies are not unified and nobody can say which technologies and which materials will be the most promising for high throughput diagnostics. 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.

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For more tutorial about microfluidics, please visit our other tutorials here: «Microfluidics tutorials». The photos in this article come from the Elveflow® data bank, Wikipedia or elsewhere if precised. Article written by Guilhem Velvé Casquillas and Timothée Houssin and revised by Lauren Durieux.

References used for this lab-on-a-chip review

[1] Lab-on-chip technologies: making a microfluidic network and coupling it into a complete microsystem—a review, P Abgrall and A-M Gue, J. Micromech. Microeng. 17 (2007) R15–R49.

[2] Lab Chip. 2014 Sep 7;14(17):3159-64. doi: 10.1039/c4lc00142g., Smartphone technology can be transformative to the deployment of lab-on-chip diagnostics., Erickson D, O’Dell D, Jiang L, Oncescu V, Gumus A, Lee S, Mancuso M, Mehta S.

[3]: Cholesterol testing on a smartphone, Vlad Oncescu,a Matthew Mancusob and  David Erickson, Lab Chip, 2014,14, 759-763.

[4]: Label-free biodetection using a smartphone, Dustin Gallegos, Kenneth D. Long,  Hojeong Yu,   Peter P. Clark,c  Yixiao Lin, Sherine George,   Pabitra Natha and Brian T. Cunningham ,Lab Chip, 2013,13, 2124-2132.

[5]: Smartphone-interfaced lab-on-a-chip devices for field-deployable enzyme-linked immunosorbent assay, Arnold Chen, Royal Wang, Candace R. S. Bever, Siyuan Xing, Bruce D. Hammock and Tingrui Pan. Biomicrofluidics 8, 064101 (2014).

[6]: http://www.ibtimes.co.uk/hiv-syphilis-can-be-detected-minutes-using-cheap-lab-chip-device-1486677

[7]: Lab-on-a-chip for continuous-flow magnetic cell separation, M Hejazian, W Li, NT Nguyen – Lab-on-a-chip, 2015.

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