Abstract
On behalf of the JALA Scientific Advisors and Editorial Board Members, I am pleased to present the honorees of the prestigious JALA Ten. Every year since 2010, JALA has highlighted the top breakthroughs across the fields of automation, drug development, diagnostics, microfluidics, bioengineering, and nanotechnology, among others, which will impact basic and translational research across the academic, government, and industry research sectors.
This year’s honorees include established investigators as well as the top emerging researchers, all of whom are leaders and rising stars within their respective fields. Their work spans the domains from single-cell interrogation to mimicking organ function as platforms for markedly improved drug-screening efficiency. For example, work from Dr. Elliot Hui’s laboratory at the University of California, Irvine has realized novel microfluidic devices for the time-lapse imaging of stem cell niches in the Caenorhabditis elegans worm model. The versatile devices developed by his team will be applicable toward areas such as cancer stem cell interrogation, wound healing, and beyond. In addition to stem cell analysis, microfluidic technology developed by the group of Dr. Donald Ingber at the Wyss Institute and Harvard Medical School has also been harnessed for the mimicry of organ systems and has resulted in the recapitulation of lung function on a chip, opening new doors for cost-effective and rapid drug development.
Although a broad range of topics is highlighted among this year’s honorees, a unifying theme is evident: High-impact innovation is often the result of multidisciplinary collaboration. This theme also serves as a foundation for JALA’s commitment to featuring scientific and technological breakthroughs that are poised to impact society through the efforts of researchers who embrace the opportunities to address challenges that may not be based upon their field of training. It is this adventurous spirit that often forges the major paradigm shifts of our generation, and we are proud to serve as a venue for honoring these thought leaders.
We at JALA and SLAS would like to thank all nominators as well as those who devoted countless hours toward the selection of The 2014 JALA Ten. We look forward to seeing what is in store for next year.
Interrogating Stem Cells with Microfluidics
Dr. Elliot Hui’s team at the University of California, Irvine developed an innovative reconfigurable microfluidic channel that is capable of high-fidelity modulation of channel width, which enabled the first time-lapse observation of the C. elegans stem cell niche. Fabricating a microchannel that is capable of studying a C. elegans worm while being amenable to pneumatic-valve integration can be particularly challenging and expensive. Dr. Hui’s team uses a rapid and scalable pencil-lead molding strategy to address this challenge. The role of stem cell niches and their importance to regulating stem cell renewal and, importantly, their behavior are gaining significant attention because these and other processes will serve as a foundation for future applications in Parkinson’s disease, cancer, wound repair, and cardiovascular and neural engineering, among other areas. Dr. Hui’s approach enables the observation of the role of the distal tip cell (DTC), which releases Notch ligands to modulate stem cell differentiation with immense detail due to the versatility of his microfluidic device ( Fig. 1 ). Because Notch signaling plays a critical role in cancer stem cell signaling, Dr. Hui’s technology platform will be appreciated by an expansive range of disciplines.
Microfluidic devices are capable of interrogating distal tip cells toward broad applications in biology and medicine. Image courtesy of Brandon Wong, 2013. Wong, B. G.; Paz, A.; Corrado, M. A.; et al. Live Imaging Reveals Active Infiltration of Mitotic Zone by Its Stem Cell Niche. Integr. Biol.
Breakthroughs in Electrochemical Sensing
Molecular analysis is often limited by diffusion of the analyte and its binding efficiency to the recognition element. These aspects represent fundamental hurdles in translational applications of microfluidics-based biosensor platforms for point-of-care diagnostics. Using a multifunctional electrode approach, researchers from the University of Arizona and Stanford University demonstrate in situ electrokinetic enhancement on a self-assembled monolayer-based electrochemical biosensor ( Fig. 2 1). The technology significantly enhances the sensitivity and reduces the total assay time for detecting strain-specific bacterial 16S rRNA toward urinary tract infection diagnostics. In follow-up studies, the team also demonstrates electrokinetics-enhanced microfluidic systems for cartridge-based pathogen identification and single-cell antimicrobial susceptibility testing ( Fig. 2 2,3). The electrokinetic technology will benefit various biosensing platforms in a wide spectrum of clinical and biochemical applications.
Innovative electrochemical sensor design enables high-sensitivity detection. Reprinted with permission from Dr. Pansy Leung, 2013. 1Sin, M. L. Y.; Liu, T. T.; Pyne, J. D.; et al. In Situ Electrokinetic Enhancement for Self-Assembled-Monolayer-Based Electrochemical Biosensing. Anal. Chem.
Detecting Mitochondrial Diseases
Fully automated, simple-to-use, molecular diagnostic systems are highly sought after for early diagnostics of a wide spectrum of diseases. For instance, the mitochondrion plays essential roles in key biological processes, such as cell cycle progression, apoptosis, and autophagy, and rapid detection of mitochondrial DNA mutation represents a critical yet highly challenging task for clinical diagnostics of mitochondrial diseases. A multidisciplinary team of researchers from Taiwan developed an integrated three-dimensional (3D) system-on-chip with modular design for direct quantitative detection of mitochondrial DNA mutation. The modular approach presented by the team dramatically simplifies the complexity of system integration, which represents one of the most critical challenges in microfluidics-based molecular diagnostic systems. Using the modular 3D system-on-chip approach, the authors demonstrate detection of mitochondrial DNA with a point mutation with high efficiency and accuracy. With its simplicity and effectiveness, the modular 3D system-on-chip approach represents a highly promising and powerful platform for early diagnostics of mitochondrial and other diseases in nontraditional healthcare settings ( Fig. 3 ).
Three-dimensional microfluidic devices can detect mitochondrial DNA mutations rapidly and with high accuracy. Reprinted with permission from Elsevier, 2013. Chang, C. M.; Chiu, L. F.; Wei, Y. H.; et al. Integrated Three-Dimensional System-on-Chip for Direct Quantitative Detection of Mitochondrial DNA Mutation in Affected Cells. Biosens. Bioelectron.
Plasmofluidic Lenses
Dr. Tony Jun Huang’s research group at The Pennsylvania State University pioneered the first plasmonic lens in a microfluidic environment, the so-called plasmofluidic lens, which is dynamically tunable and reconfigurable. The manipulation of a two-dimensional (2D) light named a surface plasmon polarition (SPP) is achieved through a vapor bubble within a liquid medium, rather than via the existing solid-state plasmonic devices that have limited tunability or reconfigurability. The surface topography, position, and shape of the plasmofluidic lens are features that collaborate to determine functionality, and they can be dynamically controlled and altered. Figure 4a shows a schematic of the reconfigurable plasmofluidic lens, wherein a laser-induced surface bubble is used to control the propagation of SPPs at the metal surface. Figure 4b–e demonstrates SPP focusing and collimation by the reconfigurable plasmofluidic lens. This novel on-chip light-manipulation mechanism enables new opportunities in developing complex biomedical detection systems with multiple functionalities, high sensitivity, and high throughput.
Schematic of the reconfigurable plasmofluidic lens developed in Huang’s group. Reprinted with permission from Nature Publishing Group, 2013. Zhao, C.; Liu, Y.; Zhao, Y.; et al. A Reconfigurable Plasmofluidic Lens. Nature Comm.
Mimicking Organs on Chip
The achievements of Dr. Donald Ingber’s team at the Wyss Institute at Harvard University demonstrate significant progress in creating physiological mimics of organ systems in vitro using combinations of cell co-cultures and microfluidic control structures. The demonstrated lung organ-on-a-chip system reaches a new level of physiological relevance in recapitulating interleukin-2 (IL2)-induced pulmonary edema and identifying drugs that interfere with the associated loss of barrier function ( Fig. 5 ). Recapitulation of breathing motion is found to be a critical aspect of the model. Such physiological microsystems are expected to be of increasing interest to pharmaceutical companies interested in early-stage disease models for drug screening that have lower cost and require less animal use.
Novel microfluidic devices are capable of mimicking organ systems for applications in drug screening. Photo courtesy of Wyss Institute at Harvard University. Reprinted with permission from the American Association for the Advancement of Science, 2012. Huh, D.; Leslie, D. C.; Matthews, B. D.; et al. A Human Disease Model of Drug Toxicity-Induced Pulmonary Edema in a Lung-on-a-Chip Microdevice. Sci. Transl. Med.
A New Generation of Materials
Although graphene remains in the news as a 2D carbon material that holds incredible promise in a wide range of applications, MXenes could also prove to be highly transformative, particularly in the development of lighter, faster, cheaper, and more efficient energy-storage devices. Functionalization of MXenes involves the intercalation of organic and inorganic compounds to form stacked sheets of MXenes. Delamination of stacked layers results in usable 2D sheets of MXenes with unique electronic properties. A team led by Dr. Yury Gogotsi of the Department of Materials Science and Engineering and the A.J. Drexel Nanotechnology Institute at Drexel University demonstrates the successful intercalation of MXenes using a wide range of compounds, including dimethyl sulfoxide. Following intercalation, the authors demonstrated the successful delamination of MXenes into paper-like, single-layer MXene flakes. Most exciting was the ability of these delaminated MXene flakes to have greater capacitive uptake of Li ions, demonstrating the potential of MXenes in the area of Li-ion battery development. Further refinement of the intercalation and delamination of MXenes should allow for the use of thin, single-layer MXene sheets in a wide range of commercial applications ( Fig. 6 ).
MXenes can serve as powerful anode materials in Li-ion batteries. Reprinted with permission from Nature Publishing Group 2013. Mashtalir, O.; Naguib, M.; Mochalin, V. N.; et al. Intercalation and Delamination of Layered Carbides and Carbonitrides. Nat Commun.
Fluorescent Nanodiamonds for Biology and Computing
Silicon-vacancy (SiV) narrowband fluorescent nanodiamonds (NDs) are gaining considerable commercial interest. Because of their optical excitation by red lasers and fluorescence in the near-infrared range, they hold particular potential in biomedical research applications when deep-tissue imaging with fluorescent probes requires minimal tissue autoflourescence and minimal absorption in tissues. A team of researchers from Germany, Switzerland, and Austria led by Dr. Anke Krueger of Universität Würzburg and Dr. Christoph Becher of Universität des Saarlandes previously reported the efficient formation of a colloidal suspension of SiV-containing NDs using bead-assisted sonic disintegration (BASD) and now further characterize the properties of these unique NDs following surface treatments and under low-temperature conditions. The team is able to identify NDs with single, bright SiV centers that fully polarize absorption and emissions ( Fig. 7 ). Thus, these NDs can be used as a single photon source and fluorescent marker, lending them to both biological applications and quantum computing.
Single nitrogen-vacancy-containing nanodiamonds processed with bead-assisted sonic disintegration (BASD) could serve as powerful materials for biology and quantum computing. Reprinted with permission from AIP Publishing 2013. Neu, E.; Guldner, F.; Arend. C.; et al. Low Temperature Investigations and Surface Treatments of Colloidal Narrowband Fluorescent Nanodiamonds. J. Appl. Phys.
Harnessing Genomic Signatures for Diagnosing and Treating Disease
As genomic sequencing becomes faster and less expensive, researchers and clinicians can begin to interrogate underlying genetic contributions to complex diseases that may not be obvious when using traditional molecular biology approaches. In particular, high-throughput sequencing is useful for analyzing and comparing genomes from a large cohort of patients. Myelodysplastic syndromes (MDS) are a heterogeneous, poorly understood group of myeloid neoplasms that are predisposed to progressing to acute myeloid leukemia. A multi-institutional team of researchers from Germany, Japan, the United States, and Singapore uses high-throughput sequencing to interrogate the genomic alterations in 944 MDS patients. Although the large cohort is widely heterogeneous, they are still able to identify 47 common mutations, including those that are associated with poor survival. As result, the researchers are able to develop a novel prognostic model that separates patients into various risk groups. This should allow clinicians to make a more informed approach to treating MDS based on a patient’s genomic signature. Similar approaches with high-throughput sequencing will prove useful in diagnosing and treating a wide variety of disease areas ( Fig. 8 ).
Identifying genetic mutations associated with poor survival can lead to higher efficacy treatment for myelodysplastic syndromes. Reprinted with permission of Nature Publishing Group, 2013. Haferlach, T.; Nagata, Y.; Grossmann, V.; et al. Landscape of Genetic Lesions in 944 Patients with Myelodysplastic Syndromes. Leukemia
Capturing Circulating Tumor Cells with Microfluidics
Isolation of circulating tumor cells (CTCs) holds the promise of noninvasive cancer detection as well as early detection of rare tumor-initiating or metastatic tumor cells. Isolated CTCs from patients can also be potentially used to evaluate therapeutic options tailored to specific patients. Due to the extreme rarity of CTCs in a heterogeneous blood specimen, a number of hurdles continue to exist when attempting to isolate CTCs from blood. In particular, high fidelity with current approaches requires very slow flow-through, which is time consuming when considering the need to process large amounts of blood for a small number of CTCs. To overcome these challenges, a team led by Dr. Jongyoon Han of MIT and Dr. Chwee Teck Lim of the National University of Singapore has designed a novel slanted spiral microfluidic approach to isolating CTCs based on their larger size. This results in an ultrafast method for CTC isolation with an efficiency of up to 87% from blood samples spiked with known cancer cell numbers. Also, all primary clinical samples were able to have CTCs extracted based on this technique, further demonstrating how this work can be translated into the clinical setting ( Fig. 9 ).
Spiral microfluidics can harness inertial forces to capture circulating tumor cells with greater efficiency. Image courtesy of Chwee Teck Lim, 2013. Warkiani. M. E.; Guan, G.; Luan K. B.; et al. Slanted Spiral Microfluidics for the Ultra-Fast, Label-Free Isolation of Circulating Tumor Cells. Lab Chip
Capturing Viable Sperm Cells with Microchannels
Many families in more developed nations are having children later in life, leading to an increased demand for in vitro fertilization (IVF) as a necessary procedure. Although IVF is relatively common, the process is still expensive and highly inefficient. A team led by Dr. Da-Jeng Yao from National Tsing Hua University in Taiwan has made significant gains in applying microfluidic technology toward enhancing the efficiency and ease with which some aspects of IVF are conducted. Microfluidic channels are used to separate motile spermatozoa from immotile ones. This is important because this improves the use of healthy active spermatozoa in the IVF procedure. Compared to traditional approaches that involve centrifugation that can damage spermatozoa, this approach is a gentle and natural isolation method. In combination with their other work in this field, these researchers should be able to bring a better, safer, more efficient method of embryo production to the standard IVF procedure ( Fig. 10 ).
Schematic illustration of the sorting process for the microfluidic system. Reprinted with permission from Sage, 2013. Huang, H. Y.; Wu, T. L.; Huang, H. R.; et al. Isolation of Motile Spermatozoa with a Microfluidic Chip Having a Surface-Modified Microchannel. J. Lab. Autom.
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Footnotes
All figures are reprinted with permission from the copyright holder.