There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

基礎講座 電気泳動(Electrophoresis)

Miniaturization can expand the capability of existing bioassays, separation technologies and chemical synthesis techniques. Although a reduction in size to the micrometre scale will usually not change the nature of molecular reactions, laws of scale for surface per volume, molecular diffusion and heat transport enable dramatic increases in throughput. Besides the many microwell-plate- or bead-based methods, microfluidic chips have been widely used to provide small volumes and fluid connections and could eventually outperform conventionally used robotic fluid handling. Moreover, completely novel applications without a macroscopic equivalent have recently been developed. This article reviews current and future applications of microfluidics and highlights the potential of 'lab-on-a-chip' technology for drug discovery.

Lab-on-a-chip: microfluidics in drug discovery.

After having reviewed some aspects of microfluidic system preparation in the first part (1), in this second part of the review we will cover a number of standard operations (namely: sample preparation, sample injection, sample manipulation, reaction, separation, and detection) as well as some biological applications of micro total analysis systems (namely: cell culture, polymerase chain reaction, DNA separation, DNA sequencing, and clinical diagnostics). As previously, we will include papers issued from different scientific journals as well as useful abstracts from three conference proceedings: MEMS, Transducers, and μTAS. In this second part, we do not include the period covered by the history section (1975-1997) from part 1 but try to cover the relevant examples of the literature published between January 1998 and March 2002. We briefly describe articles that struck us as needing special attention, while more “standard” papers are dutifully reported in groups of interest. An article might be included in more than one section, depending on the ideas developed in it.

Micro total analysis systems. 2. Analytical standard operations and applications.

This critical review summarizes developments in microfluidic platforms that enable the miniaturization, integration, automation and parallelization of (bio-)chemical assays (see S. Haeberle and R. Zengerle, Lab Chip, 2007, 7, 1094–1110, for an earlier review). In contrast to isolated application-specific solutions, a microfluidic platform provides a set of fluidic unit operations, which are designed for easy combination within a well-defined fabrication technology. This allows the easy, fast, and cost-efficient implementation of different application-specific (bio-)chemical processes. In our review we focus on recent developments from the last decade (2000s). We start with a brief introduction into technical advances, major market segments and promising applications. We continue with a detailed characterization of different microfluidic platforms, comprising a short definition, the functional principle, microfluidic unit operations, application examples as well as strengths and limitations of every platform. The microfluidic platforms in focus are lateral flow tests, linear actuated devices, pressure driven laminar flow, microfluidic large scale integration, segmented flow microfluidics, centrifugal microfluidics, electrokinetics, electrowetting, surface acoustic waves, and dedicated systems for massively parallel analysis. This review concludes with the attempt to provide a selection scheme for microfluidic platforms which is based on their characteristics according to key requirements of different applications and market segments. Applied selection criteria comprise portability, costs of instrument and disposability, sample throughput, number of parameters per sample, reagent consumption, precision, diversity of microfluidic unit operations and the flexibility in programming different liquid handling protocols (295 references).

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Microfluidic lab-on-a-chip platforms: requirements, characteristics and applications

A concept of “pinched flow fractionation” for the continuous size separation and analysis of particles in microfabricated devices has been proposed and demonstrated. In this method, particles suspended in liquid were continuously introduced into a microchannel having a pinched segment and were aligned to one sidewall in the pinched segment by another liquid flow without particles. The particles were then separated perpendicularly to the flow direction according to their sizes by the spreading flow profile inside the microchannel. Polymer microbeads were successfully separated, and the effects of the flow rate and channel shapes on the separation performance were examined. Also, separated particles were collected independently by making branches at the end of the pinched segment. Since this method utilizes only the laminar flow profile inside a microchannel, complicated outer field control could be eliminated, which is usually required for other kinds of particle separation methods such as field flow fract...

Pinched Flow Fractionation: Continuous Size Separation of Particles Utilizing a Laminar Flow Profile in a Pinched Microchannel

We propose here a new method for continuous concentration and classification of particles in microfluidic devices, named hydrodynamic filtration. When a particle is flowing in a microchannel, the center position of the particle cannot be present in a certain distance from sidewalls, which is equal to the particle radius. The proposed method utilizes this fact, and is performed using a microchannel having multiple side branch channels. By withdrawing a small amount of liquid repeatedly from the main stream through the side channels, particles are concentrated and aligned onto the sidewalls. Then the concentrated and aligned particles can be collected according to size through other side channels (selection channels) in the downstream of the microchannel. Therefore, continuous introduction of a particle suspension into the microchannel enables both particle concentration and classification at the same time. In this method, the flow profile inside a precisely fabricated microchannel determines the size limit of the filtered substances. So the filtration can be performed even when the channel widths are much larger than the particle size, without the problem of channel clogging. In this study, concentrations of polymer microspheres with diameters of 1–3 µm were increased 20–50-fold, and they were collected independently according to size. In addition, selective enrichment of leukocytes from blood was successfully performed.

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Hydrodynamic filtration for on-chip particle concentration and classification utilizing microfluidics

A new method for continuous size separation and collection of particles in microfabricated devices, asymmetric pinched flow fractionation (AsPFF), has been proposed and demonstrated. This method improves the separation scheme of pinched flow fractionation (PFF), which utilizes a laminar flow profile inside a microchannel. In this study, multiple branch channels with different channel dimensions were arranged at the end of the pinched segment, so that the flow rate distributions to each branch channel were varied, and a large part of the liquid was forced to go through one branch channel (drain channel). In the proposed channel system, the flow profile inside the microchannel was asymmetrically amplified, enabling the separation of one-order smaller particles compared with PFF. After introducing the method, we examined the effect of the asymmetric amplification by controlling the outlet of the drain channel. Also, a mixture of 1.0 ∼5.0 µm particles was separated, and erythrocytes were successfully separated from blood. The results indicate that the AsPFF method could be applied to the separation of much smaller-size particles, since more precise separation can be achieved simply by changing the geometries of branch channels.

Continuous particle separation in a microchannel having asymmetrically arranged multiple branches

Controlled formation of heterotypic hepatic micro-organoids in anisotropic hydrogel microfibers for long-term preservation of liver-specific functions

Hydrogel materials with microscale heterogeneity are of great interest in the effort to spatially control cellular microenvironments in tissue engineering applications. Here we present a microfluidic system to continuously synthesize chemically and physically anisotropic Ca–alginate hydrogel microfibers enabling the guidance of cell proliferation to form linear cell colonies and intracellular networks. The microfluidic gelation process involves 2 critical steps to obtain alginate microfibers using axisymmetric microchannels with uniform depth: introduction of a buffer solution between the sodium alginate (NaA) and CaCl2 solutions to modulate the gelation speed, and use of a thickener to balance the viscosities of the solutions. We synthesized hydrogel fibers with diameters of ∼7 to 200 μm, maintaining the anisotropy in the cross-section, and examined factors affecting the fiber diameter and uniformity. Moreover, parallel alginate flows with and without propylene glycol alginate (PGA) enabled the formation of sandwich-type solid-soft-solid hydrogel fibers, which were used to guide the direction of growth of cells inoculated in the soft-core, with the help of outer polycation membranes made of poly-L-lysine. We demonstrated the formation of linear colonies of 3T3 and HeLa cells inside the anisotropic fiber and observed elongated nuclei along the fiber direction. In addition, the heterogeneous morphology of the fiber was utilized to guide neurite elongation and generate cellular networks by using neuron-like PC12 cells. The hydrogel fibers reported here can be used as an innovative tool for investigating cell and tissue morphogenesis in heterogeneous microenvironments, and for creating tissue models with precise control of cellular alignment and elongation.

Masumi Yamada

Papers

Pinched Flow Fractionation: Continuous Size Separation of Particles Utilizing a Laminar Flow Profile in a Pinched Microchannel

Hydrodynamic filtration for on-chip particle concentration and classification utilizing microfluidics

Continuous particle separation in a microchannel having asymmetrically arranged multiple branches

Controlled formation of heterotypic hepatic micro-organoids in anisotropic hydrogel microfibers for long-term preservation of liver-specific functions

Microfluidic synthesis of chemically and physically anisotropic hydrogel microfibers for guided cell growth and networking