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Microfluidics

Introduction

Microfluidics refers to the science and technology of systems that manipulate small amounts of fluids, generally on the microliter scale and below, using fluidic structures on the sub-millimeter scale.

Numerous applications of microfluidics have been developed in chemistry (leveraging the ability to achieve rapid mixing and stable heating of reagent mixtures, for example) and in biology (leveraging the ability to handle tiny volumes or to manipulate tiny objects such as single cells, for example).

The following are good introductions to microfluidics in general:

Flow-through versus batch

An important classification of microfluidic devices for chemistry applications is whether they operate in "flow-through" or "batch" mode.  In "flow-through" mode, the reagents are continuously pumped through a reaction zone (e.g. mixer and heater). As long as reagents are pumped in, new product continues to be formed. In "batch" mode, the whole amount of reagent is loaded for each step of the synthesis process, and is reacted as a single batch. 

Flow-through devices have many advantages including superior uniformity of reaction conditions (via faster mixing and heat transfer), scalability over a wide range of production volumes, and improved safety (by reacting only a small portion of the reactants at a time).

Batch devices are better suited for multi-step processes (especially if a solvent must be removed by evaporation prior to the next step), and when the total quantity of reagents and products is very tiny.

Technology Platforms

Elastomeric microfluidic devices

Polydimethylsiloxane (PDMS) elastomer is among the most commonly used material to make microfluidic devices. Once the "master" mold has been made (e.g. using photolithography processes), PDMS replicates can easily be made without specialized equipment. Techniques have been developed for making multiple layers of channels in an elastomeric structure, which allows for the straightforward fabrication of valves and related control structures (e.g. pumps). PDMS is biocompatible and its high gas permeability and optical clarity are advantageous in many applications in biology.

The following papers show the concept, capability, and fabrication of these multi-layer devices:
  • J. Melin and S. R. Quake, Microfluidic large-scale integration: the evolution of design rules for biological automation, Annu. Rev. Biophys. Biomol. Struct., vol. 36, pp. 213–231, 2007. (Journal Link)
Chemical reactions can be performed in PDMS chips, but due to the adverse interactions of PDMS with many solvents and solutes, these applications are quite limited. The following papers describe some of the limitations of PDMS:
  • Jessamine Ng Lee,Cheolmin Park,† and, and George M. Whitesides, Solvent Compatibility of Poly(dimethylsiloxane)-Based Microfluidic Devices, Analytical Chemistry 2003 75 (23), 6544-6554 (Journal Link)
  • Rajendrani Mukhopadhyay, When PDMS isn't the best, Analytical Chemistry 2007 79 (9), 3248-3253. (Journal Link)

Electrowetting-on-dielectric (EWOD)

EWOD operation

Figure 1: Structure and operation of EWOD microfluidic chips. (A) Droplet interaction with the surface can be controlled via the “electrowetting” effect. (B) In a typical EWOD device, the droplet is sandwiched between two plates with the electrode configuration as shown. Typical dimensions of the actuation electrodes are 1 or 2 mm square, and typical droplet height (determined by spacing of the plates) is 100 µm. (C) By applying a voltage to one end of the droplet with an actuation electrode, a force is generated, pulling the droplet toward the activated electrode. (Diagram courtesy of Robin Garrell). This force enables several operations, including transport of droplets along a predetermined path, droplet splitting, and droplet dispensing from an on-chip "reservoir droplet". By incorporating specialized heating electrodes, additional operations such as solvent evaporation are possible.

EWOD, also known as digital microfluidics (DMF), relies on the electronic actuation of droplets by manipulation of surface tension or dielectrophoresis (Figure 1). For many types of liquid, an electric field can change the interaction between a droplet and the surface via the phenomenon of “electrowetting”. As electrical potential is applied to an electrode, the contact angle between the droplet and the electrode surface is reduced, thus creating a more wetting surface. Applying the potential adjacent to a droplet causes the droplet to move toward the wetted electrode. By applying a time-varying (AC) electric field, the phenomenon of dielectrophoresis can also be leveraged to create forces on droplets.  A typical EWOD chip is composed of two parallel substrates, a bottom plate containing individually-addressed actuation electrodes, and a cover plate serving as the ground electrode, with droplets sandwiched in between.  Both substrates are layered with a conductor such as indium tin oxide (ITO), a dielectric layer, and a hydrophobic layer (e.g. Cytop or Teflon), though the dielectric layer is sometimes omitted on the cover plate.  The hydrophobic layer prevents the droplet from sticking to the surface and enhances the change in contact angle upon electrical actuation, enabling many droplet-medium combinations to be manipulated e.g.: water in oil, water in air, solvent or oil in air, gas in water, etc. Solid materials (e.g. solid catalysts or magnetic beads) can also be manipulated in the form of suspensions.

By locally applying appropriate voltage sequences, numerous operations can be performed  such as droplet generation from reservoirs, droplet transport, merging of two droplets and splitting of a droplet. In chemistry applications, these basic operations enable reagent dispensing and mixing. On-chip electrodes can also be used for resistive heating and temperature sensing to achieve precise temperature control to facilitate chemical reactions. Furthermore, when the droplets are surrounded by air (versus a liquid medium such as oil), microscale versions of conventional organic synthesis processes such as evaporative solvent exchange can also be performed. Compared to other types of microfluidic devices including flow-through reactors, the open sides of the EWOD chip are advantageous for removal of solvent vapor.  

EWOD chips are often made on a glass substrate, with a metal electrode layer, an inorganic dielectric layer, and perfluoropolymer hydrophobic layer. These materials are thermally stable and the wetted components (fluoropolymer layer) is highly inert, making it suitable for chemical reactions.
 
All the liquid manipulation is performed electronically, eliminating the need for moving parts such as pumps and valves, and simplifying the chip and the external control system.

The following book chapters and articles are good introductions to EWOD microfluidics and its applications:

  • M. Abdelgawad and A. R. Wheeler, “The Digital Revolution: A New Paradigm for Microfluidics,” Advanced Materials, vol. 21, no. 8, pp. 920–925, 2009.
  • M. J. Jebrail, M. S. Bartsch, and K. D. Patel, “Digital Microfluidics: A Versatile Tool For Applications in Chemistry, Biology and Medicine,” Lab Chip, vol. 12, pp. 2452–2463, May 2012. 
  • W. C. Nelson and C.-J. “CJ” Kim, “Droplet Actuation by Electrowetting-on-Dielectric (EWOD): A Review,” Journal of Adhesion Science and Technology, vol. 26, no. 12–17, pp. 1747–1771, 2012.