Anal. Chem. 2008, 80, 4403–4419
Micro Total Analysis Systems: Latest Achievements Jonathan West, Marco Becker, Sven Tombrink, and Andreas Manz* ISAS, Institute for Analytical Sciences, Bunsen-Kirchhoff-Strasse 11, D-44139 Dortmund, Germany Review Contents Technology Microfabrication Assembly and Interfacing Optical Integration Flow Control Standard Operations Sample Preparation Injection and Separation Fluidic Reactors Particle and Cell Sorting Cell Trapping and Culture Applications Clinical Diagnostics Nucleic Acids Proteins Cell and Tissue Studies Environmental Monitoring Literature Cited
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The field of micro total analysis systems (µTAS), or “lab on a chip”, has continued to gain maturity. The importance of µTAS is reflected in both the growing number and the improved quality of articles published on this topic. µTAS touches on an incredibly diverse number of analytical chemistry applications and equally receives great input from a spectrum of scientific and engineering disciplines. In this sense, µTAS is truly interdisciplinary in nature and has served as a focal point to bring together the different research fields. For an overview of the evolving field of µTAS, readers are directed to the recent textbook by Paul Li (1). This review article aims to encapsulate the latest achievements in the field of µTAS. In this review, we provide a snapshot of this interesting time by highlighting some of the very best research papers published in the two year period between March 2006 and February 2008. This review builds on the former reviews (2–5), and together these chart the development of µTAS technologies this decade. By cross referencing online keyword searches we were able to find several thousand articles spread among a wide variety of journals, but most frequently found in the high impact journals of Analytical Chemistry and Lab on a Chip. The annual international µTAS conference also served as a great source for some of the very latest and most promising developments. Recently the topic of lab on a chip was addressed in an excellent Nature Insight supplement (6). Here, outstanding articles can be found that focus on scaling effects (7), optofluidic technologies (8), single molecule detection (9), reaction control (10), cell chips (11), and diagnostics for global public health (12). In this review, our ambition was to provide a broad overview of the novel and significant developments, both as a means to introduce newcomers and to update the more experienced with 10.1021/ac800680j CCC: $40.75 2008 American Chemical Society Published on Web 05/23/2008
the latest and cutting edge advances in the field. As with the previous reviews, we have focused on research into fluidic systems for analytical chemistry applications and in doing so chosen to omit related research in the areas of sensors, arrays (so-called “biochips”), microscale chemical synthesis, theory, and simulation as well as review and trend articles. Furthermore, the field of microfabrication is enormous and we have necessarily been sparing in our selection. Surface modification is a subject featured throughout this review. Indeed, the progress of this interdisciplinary field has made it ever difficult to draw boundaries between the different activities. In addition, by far the most dramatic trend has been the explosion of research into droplet technologies, where analytical operations can be undertaken within discrete microfluidic reaction environments. TECHNOLOGY Microfabrication. Conventional Microfabrication. There has been continued development and innovation in the area of microfabrication. Maskless photolithography using a liquid crystal display has been further improved with a sliding lens to achieve a variable resolution of 2-8 µm (13). Masks can also be prepared by metal transfer from low surface energy fluorinated ethylene propylene copolymer layers to generate microlenses and used with far-field exposure to produce nanostructures (14). For the fabrication of multiple height structures with a single exposure, Kovarik and Jacobson have exploited the size-dependent light transmission through 0.35-5.5 µm apertures (15). Microstructures with 3-D features are highly useful for µTAS operations. A multiangled backside exposure of a deep SU-8 film has been used to integrate complex micromesh structures within a microchannel (16). Tao et al. have developed a sacrificial lift-off method for the fabrication of multilayered and asymmetric SU-8 microparticles (17). Electrochemical anodization of Al2O3 produces high aspect ratio nanopores. These have been used as casting polymerization molds for the fabrication of large area nanopillar arrays (18). Printed wax structures can also function as molds, with removal simply by melting and dissolution (19). For the fabrication of 3-D microelectrode arrays, metal can be patterned by electroplating on microtowers using a mold prepared with an excimer laser (20). Yun et al. have fabricated highly aligned multiwall carbon nanotubes (MWCNTs) with huge lengths (8 mm). These remarkable dreadlock-like bundles are prepared by thermal chemical vapor deposition on Al2O3 layers doped with an iron catalyst (21). Glass is a notoriously difficult material to machine. Cathodic electrochemical discharge machining (ECDM) has been further refined for the fabrication of 3-D microstructures with vertical walls (22). While anodic ECDM also combines Analytical Chemistry, Vol. 80, No. 12, June 15, 2008
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cavitation and sputtering effects to enable the production of nanoliter volume spherical cavities (23). Alternatively, Eklund and Shkel have created arrays of spherical microstructures by wafer level glass blowing (24). In a similar fashion, bubbles with controlled dimensions can be generated in poly(dimethyl siloxane) (PDMS) (25). In the absence of masters or standard clean room lighting conditions, benzophenone can be used as a photoinitiator at
