This investment is also paying off in terms of quality and quantity of publications from this research. Lab on a Chip specifically, has seen a sharp increase in growth of content from Korea over the last few years much of it presenting a very high standard of innovation and novelty.
The following are brief biographical details of contributors to this Korean special issue who have led these developments through the pages of LOC. In addition, we wanted to get the opinions of these researchers on the whole field of microfluidics and their ideas of significant developments so we posed the following three questions to all contributors:
(1) Why are you working in this field and how did you get started?
(2) What is the most significant recent development you have seen in this field and why is it important?
(3) What factors do you think influence the lack of commercialisation of microfluidics?
Their responses to these questions, follow on from the associated author biographies below.
(1) I am always fascinated by the fact that we can make novel devices with new concepts and it is actually not only useful in many applications but also creates new ways to explore nature. I started ‘Lab-on-a-chip’ research as one of the first members of the BioMEMS group at SAIT in 1999. I was very fortunate to work together with the best group of people there and it was a truly pioneering experience for all of us.
(2) I enjoyed the work “Structural colour printing using a magnetically tunable and lithographically fixable photonic crystal” published in “Nature Photonics” in 2009 by Prof. Sunghoon Kwon's group at Seoul National University in Korea. They discovered a simple, unique and elegant way to have structural colour printing, where colour is tunable by magnetically changing the periodicity of the nanostructures using a single material and is lithographically fixable. It is attractive because it offers a new, simple, yet controllable way to have structural colour printing for a broad range of general applications.
(3) I think one important issue is the gap between “human” and “micro/nano” scale. Even though there are many examples showing unique scientific aspects of microfluidics, there has been less effort to create practical utility out of it. For example, only recently did we start to pay attention to using real clinical samples. For general users, the microfluidic devices were often not simple or cost-effective to work with. In that sense, I believe it is quite a significant accomplishment that Samsung recently launched a product, a Lab-on-a-disc blood analyzer, on to the market. I believe more of these examples will show up soon.
(1) My goal in this field is to invent a new class of the bio-inspired N/MEMS devices, capable of performing high-speed, low-power, low-cost manipulation and processing of biomolecules from the engineering implementation or inspiration of the functional structures and working principles involved in the biological systems in nano/micro-scales.
(2) In vivo-like in vitro microfluidic systems for multimodal cell characterization, capable of identifying the mechanisms and functions involved in biological interactions. In vivo-like multimodal cell simulators, resembling the cell manipulation, processing, interaction and characterization functions of biological systems, have strong potential, not only to increase the performance of in vitro microsystems, but also to solve important biomedical questions arising in personalized disease diagnosis, treatment and prevention.
(3) Firstly, the lack of close correlation between microfluidic results and clinical results. Secondly, high accuracy or sensitivity of microfluidics need to be achieved together with high selectivity and repeatability (or long-term stability) for commercial use.
(1) The subject of our research is the development of small-size real-time chemical or biological sensors. Such sensors can be readily integrated with lab-on-a-chip (LoC) systems to build portable sensing devices for various applications such as environmental safety, quick medical diagnostics, and bio-terror detection. Carbon nanotube (CNT) field effect transistor (FET) devices have several advantages for building such sensors. For example, unlike electrode-based or optical sensors, the signal-to-noise ratio of FET-based sensors does not decrease much with reduced sensor size, which is an ideal characteristic for small-size (<5 μm) sensors. However, one of the major hurdles for practical applications was the difficulty in mass-producing such devices. Since CNTs were first synthesized in a powder form, one has to assemble CNTs onto specific regions on solid substrates to build functional devices, which was not an easy task. In 2003, we developed a mass-production method for uniform quality CNT-based devices (Nature 425, 36 (2003)). We began exploring CNT-FET-based sensors, as an application for our production method, which is how this research started.
(2) For practical applications of CNT-FET-based sensors, it is crucial to integrate them with conventional silicon-based devices. We recently developed a method to produce uniform quality CNT-FET sensors for the detection of neurotransmitters and integrated them with a silicon-based signal processing chip in a single chip (LoC 10, 894 (2010)). This work is a significant development because it provides a method to integrate uniform CNT-based sensors with silicon-based signal processing circuits in a single chip, as a low-noise sensing component for LoC systems.
(3) The size of the market based solely on microfluidic technology is actually very limited. It probably includes small markets for some limited products such as purification tools and cell culture devices. For much larger markets (e.g. diagnostics, environmental safety, military, etc.), one should integrate microfluidics with other key components (e.g. sensors, signal processors). I think one of the factors influencing the lack of commercialisation of microfluidics is a lack of other key components which can be readily integrated with microfluidics to build more convenient portable systems with large markets.
(1) My eventual goal is to increase the survival rates of cancer patients using microfluidic technologies, although at the moment I focus on fundamental physics in microfluidics.
(2) I have developed microfluidic separation technologies to isolate and sort biological cells using their physico-chemical properties and hydrodynamics. Our techniques have the benefit that the biological cells of interest do not need to be labelled.
(3) At the moment, I think integration problems are the major impediments to making microfluidic devices commercialised. Integration in a single chip means the inclusion of different micro-devices such as electrodes, valves, sample reservoirs, power suppliers, etc.
(1) I found that only limited materials such as glass, Si and a few polymers had been used in the area of microfluidics. I wanted to introduce new materials in this community that had not been attempted, and I believed that new structural materials based microfluidic devices with better performance would offer new opportunities in microfluidic applications.
(2) Droplet microfluidics have given significant contributions in many different ways to save labour and time in conventional chemical and biological areas. From my own work, new polymers with a variety of properties have demonstrated improved performance as microreactors, with superior chemical and thermal resistance when compared to other polymer based microreactors.
(3) The ‘killer application’ of microfluidics has not yet arrived on the market. I think there are still some difficulties surrounding integration of all required technologies for achieving a reliable level required for commercialization. In particular, biomedical kits as a major target application do not go beyond the limitations of conventional approaches.
(1) I got started in the MEMS field, working towards the development of piezoelectric film driven micro-pumps or valves which was oriented to the inkjet printer head application, and for expanding the application field of MEMS technology to the bio or medical areas. In the beginning, we organized internal study groups for investigating much more complicated areas of the biomedical field. We then successfully developed government sponsored projects which included the development of miniaturized medical devices based on MEMS and nano technologies, and that is why I am now working in this field. I enjoy collaborating with medical doctors and other people studying in different fields.
(2) I think that the CTC counting chip reported by Prof. Toner of Harvard University is one of the most significant developments. This technology will be helpful for early diagnosis and prognosis of human cancer and also very helpful for studying metastasis of cancer.
(3) In order to commercialize microfluidic technology based products, I think that we need to concentrate more on studying user-friendly interfaces of microfluidic chips and also standardization of the technology. Another factor we need to consider is the additional development of new commercializing materials based fabrication processes for easy PDMS chip based prototype development.
(1) I work in this field because I see big opportunities now in microfluidics. The way we do biology and medicine is rapidly changing and the changes are mostly technology driven. I believe microfluidics is the engine of change. I started my research based on more traditional MEMS and semiconductor processing technologies dealing with the control of electrons. One day I realized that there are so many unknowns in biology and medicine which can be unveiled by the development of new tool kits. In most biological problems, the core is to control the direct solution phase interaction of molecules. I think that the fluidic handling problem is like Ohm's law in electronics, which we can't get away from when implementing any important systems.
(2) I think recent innovation of next generation sequencing (NGS) technologies are the most important recent development in the past ten years, since it suddenly expedited everything in biology and medicine. The big notion of personalized medicine and informatics is now widely accepted due to these developments. Most importantly, those NGS technologies showed used-to-be conservative biologists and medical doctors that technology is what they really needed to pay attention. The breaking of the conceptual barrier in translational research by NGS technology is a real innovation.
(3) I think the big wave of commercialization in microfluidics has already started. This field is pretty new and we have been accumulating quite a bit of knowledge and technological tool kits in the past ten years. Now it's time to apply those tool kits to many important problems in medicine and biology. To expedite it, we probably need to focus more on the macro-micro interface. Microfluidic systems have superior capabilities for parallel processing of many reactions, once the reactant is somehow in the channel. We see many titration assays and statistical assays in microfluidics, but seldom see microfluidics dealing with the processing of thousands of different reactants. Of interest is increasing the heterogeneity of the reactions by introducing many different molecules into the channel. Tubing and plumbing is painful and limited in scalability. We need more agile methods of inputting molecules into the channel and removing products of the reaction out of the channel.
(1) I believe that a healthy body is a basic requirement for a happy and joyful life. For this, disease prevention through early screening or diagnosis in daily life is very important. I believe that miniaturized and functionalized lab on a chip devices can provide promising and practical approaches for the accomplishment of this vision. I hope to contribute to the development of miniaturized and integrated micro-devices and systems. Towards this aim, since 2000 I have being carrying out government-funded projects for the development of key technologies for miniaturized microfluidic biosensors and systems at ETRI.
(2) There are so many important and significant developments. In my case, the camera phones and paper-based microfluidic devices reported by Prof. G. Whitesides’ group look like the most significant development, because the development proposes important and practical steps for real-world applications and commercialization together with scientific meaning.
(3) In my opinion, there are three major huddles to be overcome. First, there are still legal regulations preventing microfluidics from commercialization. Second, there is a lack of standardization of microfluidic technologies. Third, there are still many problems to be tackled scientifically and technically. Furthermore, there are practical difficulties in integrating microfluidic biosensors and systems, because these technologies are in multi-disciplinary fields and their approaches are differ greatly.
(1) I was eager for new promising technologies in the in vitro diagnostics area. I had begun to focus on finding new potential technologies that could drive rapid growth of the IVD market. Finally I found the technology area; it was lab on a chip technology.
(2) Microvalve technology is very developed. Lab on a chip devices using microvalves are close to commercialization. Commercially available lab on a chip point of care devices should be much smaller. Therefore, these instruments should be miniaturized without external pumps.
(3) Reproducibility is very important. In fact, in order to ensure reproducibility, structure, bonding and fabrication of world-to-chip technologies must be carried out correctly.
(1) We believe that a microfluidic platform for manipulation and separation has been a key technology for the realization of micro total analysis systems (μTAS) or labonachip as well as the next generation bio-tools for drug discovery, diagnostics, and tissue engineering. To develop a new platform for biological sample processing, separation, and detection, we focus on the microfluidic applications for integrative bioengineering, based on the synergetic integration of miniaturization technology to biology, chemistry, and medicine.
(2) We would like to recommend a microfluidic circuitry reported in Nature Physics (2010) by Mosadegh et al. as one of the most significant recent developments in microfluidics. By integrating elastomeric components—check-valves and switch-valves—whose functions are similar to those of a diode and a p-channel junction gate field-effect transistor in electrical circuit, respectively, they could construct a self-regulated microfluidic system, in which fluid flows are automatically and continuously operated without external control. If some challenges, including simple design scheme, reproducible mass production, and packaging issues for durability and vibration tolerance, are solved, this device-embedded flow control would be allow us to develop microfluidic integrated circuits for more practical and smarter lab on a chips.
(3) Here we would like to touch on three aspects; (I) reliable world-to-chip interfaces; (ii) integration and automation challenges; and (iii) real problems which can be solved with microfluidics. These are the challenges on the basis of two questions – Is this technology really practical and reliable for end-users? Where is this technology really useful? We believe that most end-users such as chemists, biologists, and clinicians do not want much deviation from the current state of their laboratory, which has been organized well enough to make them feel comfortable. Even in the case of patients, microfluidic technologies may be felt unnecessary or too excessively complicated for them, in the same way that smartphones often are not smart for old people. When somebody leaps out from peace and comfort, they should screw up their courage and reach a big decision. If there are no remarkable advantages and new problems which can be solved only with the newly developed technology, the infiltration of new technology into their lives is very difficult. This situation acts as a stumbling block for the commercialization of microfluidics. To overcome this, the researchers should consider again the questions mentioned above before embarking on new developments.
(1) While working with Prof. Tuan Vo Dinh, a pioneer in biosensor technology, in Oak Ridge National Laboratory I was greatly exposed to the application of miniaturization technology in the bioanalytical field. I also had the opportunity to work on nanoprobe fiber optics for imaging at single cellular level. By the time I joined SNU pharmacy school there was enormous progress in the automation of imaging science. I felt the need to develop automated and high-content imaging tools that can be quantitatively applied to cell based assays for identification of lead compounds in drug discovery.
(2) The most significant development in the field of lab on a chip is definitely the development of point of care testing (POCT) devices. Still in many parts of the world the necessary proper precautionary healthcare measures or proper treatment cannot be provided to patients simply because of lack of diagnostic tools. I firmly believe that the development of lab on a chip technology is going to be the key to powerful new diagnostic instruments. For the same reason I personally take much interest in POCT devices. Our group has already developed a portable photodiode microarray chip based on bipolar semiconductor technology, and we have shown the applicability of the chip for a number of diagnostic purposes.
(3) Microfluidics is undoubtedly a novel technology, but is fully flourished. Difficulty in controlling the structural and operational parameters at the micro scale is one of the factors that restrains the wide application of microfluidics. On the other hand, especially in the case of optical detection, the detection set up is often custom made. The requirement of a skilled hand for setting up detection systems also limits the use of microfluidics among biologists for example, as they suffer from poor signal-to-noise ratios. Although the absolute geometric accuracies and precision in microfabrication are high, they are often rather poor in a relative way, when compared to precision engineering for instance. Cost to reusability benefit of microfluidic chips also influence the lack of commercialisation of microfluidics.
(1) I strongly believe that a simple tool always works better for biological applications in terms of simple manipulation, high reproducibility, and easy accessibility for the novice. Motivated by this thought, our group has been consistently working on the integration of polymeric micro/nanostructures with microfluidics for various cell studies. The fabricated devices would simply involve well-established microfabrication and soft lithography, allowing for a low-expertise route to various polymeric microfluidic devices. The current work represents a good example of such physically modified microchannels towards high throughput single-cell analysis. With the collaboration of a cell biology expert in the School of Biological Sciences at SNU, Prof. Sang-Hyun Park, we have been working on this area for the last 5 years with particular emphasis on the development of statistically meaningful single-cell analysis tool.
(2) Recently, researchers have found that cells under apparently identical environmental conditions often display a distribution of heterogeneous responses, which is now known as “genetic noise.” To overcome the limitations of conventional flow cytometry and automated microscopy methods, microfluidic or lab on a chip platforms that can track biological responses in individual cells and monitor large populations of cells are potentially beneficial. Currently, single-cell analysis is one active research topic for microfluidics and a number of useful cell isolation and capturing methods have been introduced.
(3) In my view, the materials issue is one of the great hurdles for commercialization. PDMS is a wonder material in materials science as well as in microfluidics but some inherent properties restrict the widespread commercial use of the material. There are also other excellent materials available but it would take time to standardize and tailor material properties for each purpose. Another issue is the lack of ‘killer applications’. Although there are numerous applications for microfluidics, the market is potentially small and is not expected to grow, which is not attractive to major companies.
(1) Before I started in the lab on a chip research field, I developed various fabrication processes to contribute to a wide range of industrial issues in the framework of net shape manufacturing in various areas, such as biotechnology, electronics, automobiles, metal forming and ship-building. The developed processes handle nano, micro, meso and macro scales (nm3; trans-scale) in creating 3Dforms of various materials. For the last ten years, I have been involved in nano-stereolithography processes for the fabrication of 3D nano/micro structures for highly integrated systems. From working on the application of 3D nano/micro fabrication processes, I think that the development of effective fabrication processes with smart design is one of the essential issues in lab on a chip research. I have been making steady efforts to develop new and creative fabrication technologies for this field facing the issue of commercialization.
(2) I have paid attention to novel fabrication processes for microfluidic systems. Among the processes, paper-based microfluidic devices (suggested by Whitesides’ research group) are considered the most significant recent development.Commercialization is an important challenge in the lab on a chip research field. With respect to commercialization, the suggested development is considered as an exemplary case. Innovation of the design and the manufacturing is required for cost effectiveness and productivity towards mass production. Paper-based microfluidic devices would be commercially advantageous for some microchips for simple tests, though it seems difficult to apply to highly integrated systems.
(3) I think we need to look at the problem of “lack of commercialization of microfluidics” from a manufacturing perspective. When we look at the industries of semiconductors and displays, one might say that the advances in cost-effective manufacturing processes of highly integrated systems have significantly contributed to the dramatic growth in these areas. However, relatively few studies have been devoted to manufacturing processes for commercialization. Most processes employed in this field have been developed focusing on specific research at the laboratory level. It is considered that simplicity and integration, which would be chosen depending on the purpose of the application, are key issues in manufacturing toward commercialization. Paper-based microfluidic devices are one good example from the viewpoint of simplicity, considering the cost-effectiveness and productivity relating to mass-production. Many industrial applications could be realized by a simple device such as the paper-based microfluidic device. In addition, novel concepts for integration technology of diverse unit processes, which have been developed for a specific function or at the laboratory level, would be an important factor for the commercialization of high-functional microfluidic systems.
(1) My group had long been working on the fabrication of soft functional materials. With the emergence of microfluidic technology, we could manipulate small volumes of fluids precisely, which facilitates the design and creation of soft materials in a more controlled manner.
(2) The recent development of optofluidic devices is one of the most important progresses in lab onachip technology. The combination of two distinct technologies—microfluidics and photonics—has enabled production of novel materials in a continuous manner and analysis of various chemical and biological substances in high-throughput with enhanced resolution. In particular, integration of nanophotonic structures into microfluidic devices opened new avenues of molecular analysis and reconfigurable optics.
(3) In spite of miniaturization of microfluidic devices, the large size of the driving equipment for fluid motion (external syringes or pneumatic pumps) and characterization tools (microscopes and spectrometers) makes it impossible to produce compact and portable devices. In addition, the low chemical resistance of replicable materials limits the application area and commercialization of microfluidics.
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