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.

/pdf/microfluidics-fluid-physics-at-the-nanoliter-scale-4bpahtd8qa.pdf

Microfluidics: Fluid physics at the nanoliter scale

Hydrophilic polymers are the center of research emphasis in nanotechnology because of their perceived “intelligence”. They can be used as thin films, scaffolds, or nanoparticles in a wide range of biomedical and biological applications. Here we highlight recent developments in engineering uncrosslinked and crosslinked hydrophilic polymers for these applications. Natural, biohybrid, and synthetic hydrophilic polymers and hydrogels are analyzed and their thermodynamic responses are discussed. In addition, examples of the use of hydrogels for various therapeutic applications are given. We show how such systems’ intelligent behavior can be used in sensors, microarrays, and imaging. Finally, we outline challenges for the future in integrating hydrogels into biomedical applications.

/pdf/hydrogels-in-biology-and-medicine-from-molecular-principles-3lowrzjjsl.pdf

Hydrogels in Biology and Medicine: From Molecular Principles to Bionanotechnology†

Biomaterials have played an enormous role in the success of medical devices and drug delivery systems. We discuss here new challenges and directions in biomaterials research. These include synthetic replacements for biological tissues, designing materials for specific medical applications, and materials for new applications such as diagnostics and array technologies.

Designing materials for biology and medicine

▪ Abstract Soft lithography, a set of techniques for microfabrication, is based on printing and molding using elastomeric stamps with the patterns of interest in bas-relief. As a technique for fabricating microstructures for biological applications, soft lithography overcomes many of the shortcomings of photolithography. In particular, soft lithography offers the ability to control the molecular structure of surfaces and to pattern the complex molecules relevant to biology, to fabricate channel structures appropriate for microfluidics, and to pattern and manipulate cells. For the relatively large feature sizes used in biology (≥50 μm), production of prototype patterns and structures is convenient, inexpensive, and rapid. Self-assembled monolayers of alkanethiolates on gold are particularly easy to pattern by soft lithography, and they provide exquisite control over surface biochemistry.

/pdf/soft-lithography-in-biology-and-biochemistry-1qiku7qz44.pdf

Soft Lithography in Biology and Biochemistry

This Account summarizes techniques for fabrication and applications in biomedicine of microfluidic devices fabricated in poly(dimethylsiloxane) (PDMS). The methods and applications described focus on the exploitation of the physical and chemical properties of PDMS in the fabrication or actuation of the devices. Fabrication of channels in PDMS is simple, and it can be used to incorporate other materials and structures through encapsulation or sealing (both reversible and irreversible).

Poly(dimethylsiloxane) as a material for fabricating microfluidic devices.

Hydrogels have been developed to respond to a wide variety of stimuli, but their use in macroscopic systems has been hindered by slow response times (diffusion being the rate-limiting factor governing the swelling process) However, there are many natural examples of chemically driven actuation that rely on short diffusion paths to produce a rapid response It is therefore expected that scaling down hydrogel objects to the micrometre scale should greatly improve response times At these scales, stimuli-responsive hydrogels could enhance the capabilities of microfluidic systems by allowing self-regulated flow control Here we report the fabrication of active hydrogel components inside microchannels via direct photopatterning of a liquid phase Our approach greatly simplifies system construction and assembly as the functional components are fabricated in situ, and the stimuli-responsive hydrogel components perform both sensing and actuation functions We demonstrate significantly improved response times (less than 10 seconds) in hydrogel valves capable of autonomous control of local flow

Functional hydrogel structures for autonomous flow control inside microfluidic channels

A fully integrated biochip device that consists of microfluidic mixers, valves, pumps, channels, chambers, heaters, and DNA microarray sensors was developed to perform DNA analysis of complex biological sample solutions. Sample preparation (including magnetic bead-based cell capture, cell preconcentration and purification, and cell lysis), polymerase chain reaction, DNA hybridization, and electrochemical detection were performed in this fully automated and miniature device. Cavitation microstreaming was implemented to enhance target cell capture from whole blood samples using immunomagnetic beads and accelerate DNA hybridization reaction. Thermally actuated paraffin-based microvalves were developed to regulate flows. Electrochemical pumps and thermopneumatic pumps were integrated on the chip to provide pumping of liquid solutions. The device is completely self-contained:  no external pressure sources, fluid storage, mechanical pumps, or valves are necessary for fluid manipulation, thus eliminating possibl...

Self-contained, fully integrated biochip for sample preparation, polymerase chain reaction amplification, and DNA microarray detection.

A mixing technique based on the principle of bubble-induced acoustic microstreaming was developed. The mixer consists of a piezoelectric disk that is attached to a reaction chamber, which is designed in such a way that a set of air bubbles with desirable size is trapped in the solution. Fluidic experiments showed that air bubbles resting on a solid surface and set into vibration by the sound field generated steady circulatory flows, resulting in global convection flows and thus rapid mixing. The time to fully mix a 22 μL chamber is significantly reduced from hours (for a pure diffusion-based mixing) to tens of seconds. Numerical simulations showed that the induced flowfield and thus degree of mixing strongly depend on bubble positions. Optimal simulated mixing results were obtained for staggered bubble distribution that minimizes the number of internal flow stagnation regions. Immunomagnetic cell capture experiments showed that acoustic microstreaming provided efficient mixing
of bacterial cell (Esherichia coli K12) matrix suspended in blood with magnetic capture beads, resulting in highly effective immunomagnetic cell capture. Bacterial viability assay experiments showed that acoustic microstreaming has a relatively low shear strain field since the blood cells and bacteria remained intact after mixing. Acoustic microstreaming has many advantages over most existing chamber micromixing techniques, including simple apparatus, ease of implementation, low power consumption (2 mW), and low cost.

Bubble-induced acoustic micromixing

A microfluidic platform for the construction of microscale components and autonomous systems is presented. The platform combines liquid-phase photopolymerization, lithography, and laminar flow to allow the creation of complex and autonomous microfluidic systems. The fabrication of channels, actuators, valves, sensors, and systems is demonstrated. Construction times can be as short as 10 min, providing ultrarapid prototyping of microfluidic systems.

https://www.pnas.org/content/pnas/97/25/13488.full.pdf

Microfluidic tectonics: a comprehensive construction platform for microfluidic systems.

Several microvalves utilizing stimuli-responsive hydrogel materials have been developed. The hydrogel components are fabricated inside microchannels using a liquid phase polymerization process. In-channel processing greatly simplifies device construction, assembly, and operation since the functional components are fabricated in situ and can perform both sensing and actuation functions. Two in situ photopolymerization techniques, "laminar stream mode" and "mask mode," have been explored. Three two-dimensional (2-D) valves were fabricated and tested (response time, pressure drop, maximum differential pressure). In addition, a hydrogel/PDMS three-dimensional (3-D) hybrid valve that physically separates the sensing and regulated streams was demonstrated. Analytical modeling was performed on the 3-D valve. Hydrogel-based microvalves have a number of advantages over conventional microvalves, including relatively simple fabrication, no external power requirement, no integrated electronics, large displacement (185 /spl mu/m), and large force generation (22 mN).

Robin H. Liu

Papers

Functional hydrogel structures for autonomous flow control inside microfluidic channels

Self-contained, fully integrated biochip for sample preparation, polymerase chain reaction amplification, and DNA microarray detection.

Bubble-induced acoustic micromixing

Microfluidic tectonics: a comprehensive construction platform for microfluidic systems.

Fabrication and characterization of hydrogel-based microvalves