Microfluidics has become today’s platform technology for the precise control and manipulation of fluids on the micrometer scale. 8 The term ‘microfluidics’ originates from the combination of microfabrication techniques such as soft lithography with the fluid dynamics on the micrometer scale. 10,55-57 Accordingly, small amounts of fluids ( to liters) are handled and manipulated using channels with dimensions of tens to hundreds of micrometers.
58 Hence, the biggest advantage of microfluidics lies in the micrometer dimensions of the channels and the related fluid dynamic implications for the samples such as laminar flow or diffusion-based mixing. These fundamental physical properties at the micron scale enabled the evolution of a variety of microfluidic tools. As an example, these tools can be highly
beneficial for the precise study of nucleation and growth processes and the fast and efficient screening of experimental conditions, like i.e. pH, ionic strength, species compositions, shear forces, cosolvents and concentration. 58
In the beginnings of this technology, the microfabrication of these small channels has been strongly influenced by the field of microelectromechanical systems (MEMS) that involves electronic circuits, sensors and micromechanical components. 58-61 This field offers a rich portfolio of available glass- and silicon-related fabrication techniques which stimulated the early development of microfluidics. 58 Today, the most used microfluidic device fabrication technique is soft lithography which is the combination of soft materials such as polydimethylsiloxane (PDMS) with photolithography. 55,56,62,63 These fabrication methods and more device materials will be discussed in greater detail in the chapters 2 and 4.
The closely related terms ‘miniaturized total analysis systems’ (µTAS) or ‘lab on a chip’
originate from the 1990s. 64 They describe the concept of combining the elements of microchemical ‘factories’ on a small, single chip which can incorporate functional elements such as pumps, valves, mixers, switches, heaters, multiplexers, electrodes and sensors. 8,58,65-83 Consequently, the ‘lab on a chip’ concept aims towards the increase of mobility and the reduction of energy consumption, waste production and ultimately production costs by eliminating the need for traditional laboratory equipment. 64 This idea has been demonstrated for complicated chemical reactions and complex microchannel networks that combine multiple functional elements on a single chip. 67,79 The concept of a micro reaction plant on a chip has also been demonstrated for complex reactions like the living anionic polymerization of block copolymers with direct on-chip DLS analysis of the resulting micelles. Another complicated reaction on a chip has been demonstrated for the synthesis of 18F-labeled organic compounds that are used in positron emission tomography (PET). 58,81,84,85
Additionally to the already-mentioned features of microfludics that include low sample consumption, the beneficial features of microfluidics also include the integration of functional elements on a chip which enable small device footprints. Further, the fabrication costs are typically small, the waste production is minimized and it is also possible to run exothermic reactions while maintaining temperature control. 86,87 This great temperature control is enabled by to the small amounts of reacting mass combined with the high surface to volume ratio of the microchannel network. As a consequence, safe operation is guaranteed while the uniform heat transfer also gives great control over the reaction kinetics. 86,87 Further examples include the production of microparticles and nanoparticles with a large diversity of morphologies and physicochemical properties with respect to size, shape, surface charge and amphilicity. 88-96. Although the volumes of the handled fluids are typically small, the massive parallelization of microfluidic devices offers the potential of upscaling the processes to industrial scales. 97
Microfluidic technology also offers many advantages when it comes to sample analysis and, consequently, today’s list of developed applications for microfluidic platforms is manifold. 58 For example, sample analysis related demonstrations include “separations coupled to mass spectroscopy, high-throughput screening in drug development, bioanalyses, examination and manipulation of samples consisting of a single cell or a single molecule“.58,74,96,98-101 Further, applications include processes such as free-flow electrophoresis or blood sample analysis which have been improved and miniaturized. 102,103 Together with the above-described functional elements, like valves and pumps, combinatoric experiments and high-throughput reaction screenings became possible 67,79,104,105 As an example, Quake et al. developed methods for the microfluidic large scale integration which is the microfluidic analogue to the technological jump from single transitors to microprocessors in electrical engineering. 67,104 Through microfluidic valves, pumps, and multiplexers, this technology enables combinatorics and high-throughput screenings (HTS) for single cell analysis, deoxyribonucleic acid (DNA) synthesis, digital polymerase chain reaction (dPCR), genome sequencing, as well as and large scale genomics and proteomics. 80,106-117 Furthermore, this HTS-approach also allows to find and optimize protein crystallization conditions while only requiring very small amounts of sample. 118-121
Figure 2 Illustration of the microfluidic large scale integration concept. 67,79,104 (A,B) The flow and mixing of samples with nanoliter volumes are controlled using small valves and pumps.
Accordingly, the resulting device footprint is very small (C) and the computer-controlled devices can handy very complex tasks such as the high-throughput screening of fluorescence-based single-cell assays (D). (Images from 67(A,B, Copyright Science), 79 (C, D, Copyright Nature))
Another example for microfluidic condition screening and combinatorics is the crystallization of single protein crystals. A wide range of microfluidic tools have been developed for this purpose due to this field’s great importance for medicine and the life sciences. 119,120,122-128 These examples show that it is possible to generate screening libraries for the automated crystallization of enzymes, proteins and other substances under defined conditions in droplets of individually addressable, on-chip microcompartments while only requiring very small amounts of sample.
All these examples demonstrate that microfluidics offers great control over fluids, reactions and experimental conditions by taking advantage of the fluid dynamics on the micrometer scale that enable laminar flow and diffusive mixing. 10 In combination with the above-mentioned microfocus X-ray techniques, many new experimental opportunities arise which would not be possible with conventional macroscopic systems.
However, the transfer of microfluidic technology to X-ray experiments is technically very challenging due to the X-ray compatibility of the different device materials. In this ongoing transfer process, a variety of fabrication approaches and multiple device types have been developed. The next chapter will review these available X-ray compatible device types and describe the studies that have been performed at microfocus X-ray sources.