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Review
. 2013 Jan 15;85(2):451-72.
doi: 10.1021/ac3031543. Epub 2012 Dec 4.

Micro total analysis systems: fundamental advances and applications in the laboratory, clinic, and field

Michelle L Kovarik  1 , Douglas M Ornoff, Adam T Melvin, Nicholas C Dobes, Yuli Wang, Alexandra J Dickinson, Philip C Gach, Pavak K Shah, Nancy L Allbritton
Affiliations
Review

Micro total analysis systems: fundamental advances and applications in the laboratory, clinic, and field

Michelle L Kovarik et al. Anal Chem. .
No abstract available

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Figures

Figure 1
Figure 1
Recent fundamental advances included (a) new microfabrication methods, (b) integration with acoustics, and (c) integration with biomimetic mechanical systems. (a) An illustration of a self-assembling microfluidic device with PDMS channels integrated with a differentially crosslinked SU-8 film attached to a silicon substrate. From ref . Reprinted with permission from Nature Publishing Group. (b) Acoustic tweezers with orthogonal pairs of chirped interdigital transducers for generating a standing surface acoustic wave field. Reprinted with permission from ref . Copyright 2012 National Academy of Sciences. (c) A soft robot glowing in the dark using chemiluminescence. (Inset) The same robot photographed in the light. From ref . Reprinted with permission from AAAS.
Figure 2
Figure 2
Recent devices used microfluidics to dispense liquids accurately off-chip with applications in (a, b) cell-based assays and (c) scanning electrochemical microscopy. (a) This valve-less, single channel pipette sequentially dispensed capsaicin and calcium for signaling studies in single cells. Reproduced from ref with permission of The Royal Society of Chemistry. (b) A multichannel dispenser applied reagents to low-volume cell cultures. Reprinted from ref . Copyright 2012 American Chemical Society. (c) A push-pull probe provided a continuously renewed droplet of redox mediators for scanning electrochemical microscopy. Reprinted from ref . Copyright 2011 American Chemical Society.
Figure 3
Figure 3
On-chip synthesis. Microfluidic systems allowed for (a) continuous protein production, (b) bicompartmental synthesis, (c) combinatorial synthesis, (d) mimicking of plant photosynthesis and (e) synthesis of 3D solids. (a) Flow-based continuous cell-free protein synthesis was performed in 40-μm diameter, 15-μm tall reaction vessels that contained DNA templates and translation components. Reactants were delivered via flow, and synthesized proteins were released through the container pores. From ref . Reproduced with permission of The Royal Society of Chemistry. (b) Bicompartmental droplets allowed analyte transport into an ionic liquid droplet to produce a fluorescent product that could be decoupled from the combined droplets. From ref . Copyright 2012 John Wiley & Sons, Inc. (c) A microfluidic device for combinatorial synthesis by droplet fusion utilized multiple droplet injection regions and electrocoalescence-based droplet fusion. From ref . Reproduced with permission of The Royal Society of Chemistry. (d) A microfluidic mimic of natural photosynthesis incorporated CdSe quantum dots for light-dependent reaction regions separate from light-independent reaction regions. From ref . Reproduced with permission of The Royal Society of Chemistry. (e) A microfluidic device utilized two-photon continuous flow lithography to produce 3D structures. From ref . Copyright 2012 John Wiley & Sons, Inc.
Figure 4
Figure 4
Digitization advances included new means of droplet (a) generation and (b, c, d) manipulation as well as (e) high-density digital PCR. (a) A dual-coaxial microfluidic device produced gas/liquid/liquid double emulsions with a high degree of emulsion/droplet control. From ref . Reproduced with permission of The Royal Society of Chemistry. (b) A grid of electrodes allowed reagent actuation to the site of a dried blood spot for the quantification of amino acids in blood via in-line mass spectrometry. From ref . Reproduced with permission of The Royal Society of Chemistry. (c) Utilizing a silane-patterned open-surface microfluidics device, droplets containing an insoluble surfactant (green) were self-propelled along a sub-phase liquid (blue). From ref . Reproduced with permission of The Royal Society of Chemistry. (d) Electrowetting forces laterally spread droplets. Upon removal of electrowetting forces, the droplets converted stored energy to kinetic energy, causing them to “jump” off the surface. Reprinted with permission from Lee, S., Lee, S. & Kang, K. Droplet jumping by electrowetting and its application to the three-dimensional digital microfluidics. Appl. Phys. Lett.100, 081604. Copyright 2012, American Institute of Physics (ref 123). (e) High-density digitization of PCR samples into microscale compartments. This “megapixel” digital PCR device had reaction vessel densities exceeding 440,000 cm−2 and a dynamic range of 107. Reproduced from ref with permission of the Nature Publishing Group.
Figure 5
Figure 5
Control of the cellular microenvironment. μTAS technology enabled new studies in a variety of biological systems. (a) Selective release and tracking of newly-budded yeast daughter cells across multiple generations controlled by microfluidic flow. Reprinted with permission from ref . Copyright 2012 National Academy of Sciences. (b) A microfluidic maze established tunable EGF gradients on the cellular level to study epithelial cell migration. From ref . Reproduced with permission of the Royal Society of Chemistry. (c) Chemokine-induced adenoid cystic carcinoma intravasation through a mock endothelial cell monolayer in microfluidic-based device. Scale bar, 200 μm. From ref . Adapted by permission from the Royal Society of Chemistry.
Figure 6
Figure 6
Organs and organisms-on-chip. Microfluidics allowed controlled studies of (a,b) cell-cell interactions and (c) whole organisms. (a) Time-lapse images of a red blood cells flowing through a capillary network developed from endothelial cells cultured in a microfluidic channel. From ref . Reproduced with permission of The Royal Society of Chemistry. (b) Sprouting of mCherry-expressing endothelial cells (arrowheads) from a central lumen was demonstrated within a co-culture of 10T1/2 cells expressing enhanced green fluorescent protein. Scale bar, 200 μm. Adapted by permission from Macmillan Publishers Ltd: Nature Materials, ref , copyright 2012. (c) A microfluidic device for examining behavioral responses of C. elegans to chemical changes. Scale bars, 500 μm. Adapted by permission from Macmillan Publishers Ltd: Nature Methods, ref , copyright 2012.
Figure 7
Figure 7
Clinically-relevant microfluidic devices for (a, b) whole cell analyses and (c) easy readout. (a) Hydrodynamic pressure applied to cells from the chest wall of patients allowed identification of malignancy by monitoring the mechanical deformability of single cells at a rate of 2000 cells/s. Reproduced from ref . Copyright 2012, National Academy of Sciences, USA. (b) A microfluidic device for ELISA-based measurements from whole blood. The device separated plasma from red blood cells for subsequent immunosensing. The serpentine channels also allowed for quantification of serum hematocrit, based on the length of the packed red blood cells. Reproduced from ref with permission of The Royal Society of Chemistry. (c) Antigen-responsive microfluidic valves for easily interpreted results. Introduction of an antigen into an antibody-packed column led to polymerization and blockage of subsequent flow, which was used to visualize test results. Reproduced from ref with permission of The Royal Society of Chemistry.
Figure 8
Figure 8
(a) Nucleic acid amplification and (b, c) immunosensing-based microfluidic devices for clinical use. (a) Integrated platform for detecting drug resistance genotypes in Mycobacterium tuberculosis. The system incorporated a cell lysis region, PCR amplification and LDR-based detection with integrated optics. Reproduced from ref with permission of The Royal Society of Chemistry. (b) Immunosensing ELISA performed on a lab-on-a-disc to measure levels of human C-reactive protein, cardiac troponin I, or N-terminal prohormone of brain natriuretic peptide. Reproduced from ref . Copyright 2012 American Chemical Society. (c) Immunosensing device for detecting infectious microorganisms (HIV and Treponema pallidum, which causes syphilis). This device was field-tested in resource-poor areas of Rwanda. Reproduced from ref . Adapted by permission from Macmillan Publishers Ltd: Nature Medicine, copyright 2012.
Figure 9
Figure 9
These highly portable devices are suitable for use in the field. (a) A self-powered microfluidic device that included a methanol fuel cell. Reproduced from ref with permission of The Royal Society of Chemistry. (b) An on-chip distiller for measuring SO2 concentrations in wine at the production or bottling site. Reproduced from ref with permission of The Royal Society of Chemistry. (c) An integrated immunoassay device for monitoring algal cyanotoxins in natural waters. Reproduced from ref with permission of The Royal Society of Chemistry.
Figure 10
Figure 10
μTAS have been designed for deployment in highly challenging environments, including (a) the ocean, (b) hot springs, and (c) outer space. (a) A submersible microfluidic device for detecting explosive compounds in the ocean. Reprinted from ref . Copyright 2011 American Chemical Society. (b) A pressurized vessel containing a photomultiplier tube, electronics, and a microfluidic device for measuring microbial activity in a shallow hot spring. Reproduced from ref with permission of The Royal Society of Chemistry. (c) A microfluidic device for voltage clamp studies of oocytes during parabolic flight. Reproduced from ref with permission of The Royal Society of Chemistry.
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