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

Key Points

  • Miniaturization from conventional to small size results in several advantages, such as reduced sample consumption and shortened transport times of mass and heat.

  • A key feature in microfluidic systems is the integration of different functional units for reaction, separation and detection in a channel network. Therefore, serial processing and analysis could be easily performed in the flowing systems. Furthermore, because space is used sparingly, massive parallelization can be accomplished.

  • In microfluidic chips, chemical syntheses can be performed. Concentration of reagents and temperature can be regulated precisely. Operating under continuous flow conditions will also allow the combination of multiple reaction steps and on-line analysis on one single chip. Serial and parallel solution-phase synthesis is demonstrated in microchips.

  • Microfluidic screening and sorting devices have been developed that offer the benefits of a continuous operation, including reaction steps preceding as well as succeeding the sorting process. In combination with appropriate biological assays and high-sensitivity detection techniques, such systems allows the identification and isolation of individual cells or molecules.

  • Microfluidic chips facilitate the generation and handling of nano- and picolitre liquid volumes. By injecting the aqueous phase into the stream of the carrier medium at a T-junction or by applying focussing techniques, small reaction chambers ('droplets') are generated. The precisely controllable supply of reagents, handling of small liquid volumes devoid of fast evaporation as well as the high-speed formation of droplets with a homogeneous diameter of a few μm makes this approach a valuable tool for screening experiments that rely on high reproducibility.

  • By generating technologies with nanoscale dimensions, reaction volumes are being achieved similar to those typically found in biological systems such as living cells. Recent studies show the possibility of using microfluidic platforms for cell culturing and observation and being able to manipulate living cells individually. Using microfluidics, cells could be locally stimulated, for example, to study the effect of drug levels on chemotaxis of living cells in vitro.

  • In key issues of drug discovery, such as chemical synthesis, screening of compounds and preclinical testing of drugs on living cells, microfluidic tools can meet the demands for high throughput, and can improve or might eventually replace existing technologies.

Abstract

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.

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Figure 1: Microfluidics in drug discovery.
Figure 2: Combinatorial syntheses in microfluidic chips.
Figure 3: Screening in microdroplets.
Figure 4: Trapping cells for large-scale single-cell analysis.

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Acknowledgements

Financial support by the European Community (CellPROM project, contract No., NMP4-CT-2004-500039), by the Ministerium für Innovation, Wissenschaft, Forschung und Technologie des Landes Nordrhein-Westfallen and by the Bundesministerium für Bildung und Forschung is gratefully acknowledged. We thank all group members and A. J. Garman (AstraZeneca) for helpful discussions and K. Tachikawa for proofreading of the manuscript.

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Glossary

Electrophoresis

The motion of charged particles in an electrical field towards the opposite electrode.

Photolithography

A fabrication technique to generate small features in micrometre dimensions on microchip substrates such as silicon, glass or polymers.

Total internal reflection microscopy

An optical method to image fluorescent samples at interfaces, such as in proximity to a glass surface.

Ugi multicomponent condensation

An organic reaction between a ketone or aldehyde, an isocyanide, an amine and a carboxylic acid to form a bis-amide. Libraries of low-molecular-mass drug-like compounds can be generated via the Ugi multicomponent condensation.

Dielectrophoresis

The repulsion or attraction of particles in a non-uniform electrical field based on polarization effects.

Electro-osmotic flow

A method to induce flow in a microchannel. An ionic double layer is present at the interface of the (immobile) microchannel (with charged surface) and the mobile fluid (counter-ions are accumulated near the channel surface). Application of an electrical field along the microchannel causes the dissolved ions, together with the bulk fluid, to move to the respective electrode.

Focusing techniques

Narrowing of a fluid stream by applying a sheath flow, for example, in a crossed channel geometry.

Segmented flow

Flow of alternating plugs (droplets) of two immiscible liquids or a liquid and a gas.

Laminar flow

In the laminar flow regime, no turbulence is observed. As a consequence, two merging fluid streams are flowing in parallel, so that mixing occurs only by diffusion.

Interfaces

The connection between a microchip and its features to a macroscopic system, such as microscopic stages, tubing systems and wiring interconnections.

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Dittrich, P., Manz, A. Lab-on-a-chip: microfluidics in drug discovery. Nat Rev Drug Discov 5, 210–218 (2006). https://doi.org/10.1038/nrd1985

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