Microfabricated integrated circuits revolutionized computation by vastly reducing the space, labor, and time required for calculations. Microfluidic systems hold similar promise for the large-scale automation of chemistry and biology, suggesting the possibility of numerous experiments performed rapidly and in parallel, while consuming little reagent. While it is too early to tell whether such a vision will be realized, significant progress has been achieved, and various applications of significant scientific and practical interest have been developed. Here a review of the physics of small volumes (nanoliters) of fluids is presented, as parametrized by a series of dimensionless numbers expressing the relative importance of various physical phenomena. Specifically, this review explores the Reynolds number Re, addressing inertial effects; the Peclet number Pe, which concerns convective and diffusive transport; the capillary number Ca expressing the importance of interfacial tension; the Deborah, Weissenberg, and elasticity numbers De, Wi, and El, describing elastic effects due to deformable microstructural elements like polymers; the Grashof and Rayleigh numbers Gr and Ra, describing density-driven flows; and the Knudsen number, describing the importance of noncontinuum molecular effects. Furthermore, the long-range nature of viscous flows and the small device dimensions inherent in microfluidics mean that the influence of boundaries is typically significant. A variety of strategies have been developed to manipulate fluids by exploiting boundary effects; among these are electrokinetic effects, acoustic streaming, and fluid-structure interactions. The goal is to describe the physics behind the rich variety of fluid phenomena occurring on the nanoliter scale using simple scaling arguments, with the hopes of developing an intuitive sense for this occasionally counterintuitive world.

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Microfluidics: Fluid physics at the nanoliter scale

Microfluidic devices for manipulating fluids are widespread and finding uses in many scientific and industrial contexts. Their design often requires unusual geometries and the interplay of multiple physical effects such as pressure gradients, electrokinetics, and capillarity. These circumstances lead to interesting variants of well-studied fluid dynamical problems and some new fluid responses. We provide an overview of flows in microdevices with focus on electrokinetics, mixing and dispersion, and multiphase flows. We highlight topics important for the description of the fluid dynamics: driving forces, geometry, and the chemical characteristics of surfaces.

Engineering flows in small devices

The suitability of electrowetting-on-dielectric (EWD) microfluidics for true lab-on-a-chip applications is discussed. The wide diversity in biomedical applications can be parsed into manageable components and assembled into architecture that requires the advantages of being programmable, reconfigurable, and reusable. This capability opens the possibility of handling all of the protocols that a given laboratory application or a class of applications would require. And, it provides a path toward realizing the true lab-on-a-chip. However, this capability can only be realized with a complete set of elemental fluidic components that support all of the required fluidic operations. Architectural choices are described along with the realization of various biomedical fluidic functions implemented in on-chip electrowetting operations. The current status of this EWD toolkit is discussed. However, the question remains: which applications can be performed on a digital microfluidic platform? And, are there other advantages offered by electrowetting technology, such as the programming of different fluidic functions on a common platform (reconfigurability)? To understand the opportunities and limitations of EWD microfluidics, this paper looks at the development of lab-on-chip applications in a hierarchical approach. Diverse applications in biotechnology, for example, will serve as the basis for the requirements for electrowetting devices. These applications drive a set of biomedical fluidic functions required to perform an application, such as cell lysing, molecular separation, or analysis. In turn, each fluidic function encompasses a set of elemental operations, such as transport, mixing, or dispensing. These elemental operations are performed on an elemental set of components, such as electrode arrays, separation columns, or reservoirs. Examples of the incorporation of these principles in complex biomedical applications are described.

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Digital microfluidics: is a true lab-on-a-chip possible?

This review comprises a detailed survey of ongoing methodologies for soft actuators, highlighting approaches suitable for nanometer- to centimeter-scale robotic applications. Soft robots present a special design challenge in that their actuation and sensing mechanisms are often highly integrated with the robot body and overall functionality. When less than a centimeter, they belong to an even more special subcategory of robots or devices, in that they often lack on-board power, sensing, computation, and control. Soft, active materials are particularly well suited for this task, with a wide range of stimulants and a number of impressive examples, demonstrating large deformations, high motion complexities, and varied multifunctionality. Recent research includes both the development of new materials and composites, as well as novel implementations leveraging the unique properties of soft materials.

Soft Actuators for Small-Scale Robotics.

Point of care testing is playing an increasingly important role in improving the clinical outcome in health care management. The salient features of a point of care device are rapid results, integrated sample preparation and processing, small sample volumes, portability, multifunctionality and low cost. In this paper, we demonstrate some of these salient features utilizing an electrowetting-based Digital Microfluidic platform. We demonstrate the performance of magnetic bead-based immunoassays (cardiac troponin I) on a digital microfluidic cartridge in less than 8 minutes using whole blood samples. Using the same microfluidic cartridge, a 40-cycle real-time polymerase chain reaction was performed within 12 minutes by shuttling a droplet between two thermal zones. We further demonstrate, on the same cartridge, the capability to perform sample preparation for bacterial infectious disease pathogen, methicillin-resistant Staphylococcus aureus and for human genomic DNA using magnetic beads. In addition to rapid results and integrated sample preparation, electrowetting-based digital microfluidic instruments are highly portable because fluid pumping is performed electronically. All the digital microfluidic chips presented here were fabricated on printed circuit boards utilizing mass production techniques that keep the cost of the chip low. Due to the modularity and scalability afforded by digital microfluidics, multifunctional testing capability, such as combinations within and between immunoassays, DNA amplification, and enzymatic assays, can be brought to the point of care at a relatively low cost because a single chip can be configured in software for different assays required along the path of care.

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Development of a digital microfluidic platform for point of care testing

We have designed a microfluidic device for the actuation of liquid droplets or continuous streams on a solid surface by means of integrated microheater arrays. The microheaters provide control of the surface temperature distribution with high spatial resolution. These temperature gradients locally alter the surface tension along droplets and thin films thus propelling the liquid toward the colder regions. In combination with liquophilic and liquophobic chemical surface patterning, this device can be used as a logistic platform for the parallel and automated routing, mixing and reacting of a multitude of liquid samples, including alkanes, poly(ethylene glycol) and water.

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Thermocapillary actuation of droplets on chemically patterned surfaces by programmable microheater arrays

We demonstrate the active manipulation of nanoliter liquid samples on the surface of a glass or silicon substrate by combining chemical surface patterning with electronically addressable microheater arrays. Hydrophilic lanes designate the possible routes for liquid migration while activation of specific heater elements determine the trajectories. The induced temperature fields spatially modulate the liquid surface tension thereby providing electronic control over the direction, timing, and flow rate of continuous streams or discrete drops. Temperature maps can be programed to move, split, trap, and mix ultrasmall volumes without mechanically moving parts and with low operating voltages of 2–3 V. This method of fluidic actuation allows direct accessibility to liquid samples for handling and diagnostic purposes and provides an attractive platform for palm-sized and battery-powered analysis and synthesis.

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Microfluidic actuation by modulation of surface stresses

We provide guidelines for the design and operation of a planar digital nanodispensing system based on thermocapillary actuation. Thin metallic microheaters embedded within a chemically patterned glass substrate are electronically activated to generate and control 2D surface temperature distributions which either arrest or trigger liquid flow and droplet formation on demand. This flow control is a consequence of the variation of a liquid's surface tension with temperature, which is used to draw liquid toward cooler regions of the supporting substrate. A liquid sample consisting of several microliters is placed on a flat rectangular supply cell defined by chemical patterning. Thermocapillary switches are then activated to extract a slender fluid filament from the cell and to divide the filament into an array of droplets whose position and volume are digitally controlled. Experimental results for the power required to extract a filament and to divide it into two or more droplets as a function of geometric and operating parameters are in excellent agreement with hydrodynamic simulations. The capability to dispense ultralow volumes onto a 2D substrate extends the functionality of microfluidic devices based on thermocapillary actuation previously shown effective in routing and mixing nanoliter liquid samples on glass or silicon substrates.

Planar digital nanoliter dispensing system based on thermocapillary actuation

We demonstrate a nonintrusive optical method for microfluidic detection and analysis based on evanescent wave sensing. The device consists of a planar thin-film waveguide integrated with a microfluidic chip for directed surface flow. Microliter droplets are electronically transported and positioned over the waveguide surface by thermocapillary actuation. The attenuated intensity of propagating modes is used to detect droplet location, to monitor dye concentration in aqueous solutions, and to measure reaction rates with increasing surface temperature for a chromogenic biochemical assay. This study illustrates a few of the capabilities possible by direct integration of optical sensing with surface-directed fluidic devices.

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Microfluidic detection and analysis by integration of thermocapillary actuation with a thin-film optical waveguide

We demonstrate a microfluidic actuation technique capable of directing nanoliter liquid samples on the surface of a glass substrate through the use of both electronically addressable heater arrays and chemical patterning. Pathways for liquid movement are delineated by the arrangement of microheaters, which also provide the thermocapillary actuating force. The drops are confined by selectively depositing a fluorinated monolayer to the surface, which defines the channel edges. Operating voltages in the range of 2-3V were used to move, split, and trap liquids. This fluid transportation technique enables direct access to liquid samples for handling and diagnostic purposes and offers a low power alternative to existing microfluidic systems.

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Joseph P. Valentino

Papers

Thermocapillary actuation of droplets on chemically patterned surfaces by programmable microheater arrays

Microfluidic actuation by modulation of surface stresses

Planar digital nanoliter dispensing system based on thermocapillary actuation

Microfluidic detection and analysis by integration of thermocapillary actuation with a thin-film optical waveguide

Thermocapillary actuation of liquids using patterned microheater arrays