The increasingly narrow and brilliant beams at X-ray facilities reduce the requirements for both sample volume and data acquisition time. This creates new possibilities for the types and number of sample conditions that can be examined but simultaneously increases the demands in terms of sample preparation. Microfluidic-based sample preparation techniques have emerged as elegant alternatives that can be integrated directly into the experimental X-ray setup remedying several shortcomings of more traditional methods. We review the use of microfluidic devices in conjunction with X-ray measurements at synchrotron facilities in the context of 1) mapping large parameter spaces, 2) performing time resolved studies of mixing-induced kinetics, and 3) manipulating/processing samples in ways which are more demanding or not accessible on the macroscale. The review covers the past 15 years and focuses on applications where synchrotron data collection is performed in situ, i.e. directly on the microfluidic platform or on a sample jet from the microfluidic device. Considerations such as the choice of materials and microfluidic designs are addressed. The combination of microfluidic devices and measurements at large scale X-ray facilities is still emerging and far from mature, but it definitely offers an exciting array of new possibilities.

A microfluidic platform combined with synchrotron small-angle X-ray scattering (SAXS) was used for monitoring the continuous production of multilamellar vesicles (MLVs). Their production was fast and started to evolve within less than 0.43 s of contact between the lipids and the aqueous phase. To obtain nanoparticles with a narrow size distribution, it was important to use a modified hydrodynamic flow focusing (HFF) microfluidic device with narrower microchannels than those normally used for SAXS experiments. Monodispersed MLVs as small as 160 nm in size, with a polydispersity index (PDI) of approximately 0.15 were achieved. The nanoparticles produced were smaller and had a narrower size distribution than those obtained via conventional bulk mixing methods. This microfluidic platform therefore has a great potential for the continuous production of monodispersed NPs.

A simple process for the microfluidic synthesis of hexosomes based on docosahexaenoic acid monoglyceride (MAG-DHA) with narrow size distributions.

This article introduces a simple microfluidic device that can be combined with synchrotron small‐angle X‐ray scattering (SAXS) for monitoring dynamic structural transitions. The microfluidic device is a thiol–ene‐based system equipped with 125 µm‐thick polystyrene windows, which are suitable for X‐ray experiments. The device was prepared by soft lithography using elastomeric molds followed by a simple UV‐initiated curing step to polymerize the chip material and simultaneously seal the device with the polystyrene windows. The microfluidic device was successfully used to explore the dynamics of the structural transitions of phytantriol/dioleoylphosphatidylglycerol‐based cubosomes on exposure to a buffer containing calcium ions. The resulting SAXS data were resolved in the time frame between 0.5 and 5.5 s, and a calcium‐triggered structural transition from an internal inverted‐type cubic phase of symmetry Im3m to an internal inverted‐type cubic phase of symmetry Pn3m was detected. The combination of microfluidics with X‐ray techniques opens the door to the investigation of early dynamic structural transitions, which is not possible with conventional techniques such as glass flow cells. The combination of microfluidics with X‐ray techniques can be used for investigating protein unfolding, for monitoring the formation of nanoparticles in real time, and for other biomedical and pharmaceutical investigations.

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