Fifteen years ago, surface acoustic waves (SAW) were found to be able to drive fluids and numerous applications in microfluidics have been developed since. Here, we review the progress made and report on new approaches in setting-up microfluidic, continuous flow acoustic mixing. In a microchannel, chaotic advection is achieved by generation of a SAW driven fluid jet perpendicular to the mean flow direction. Using a high speed video camera and particle image velocimetry, we measure the flow velocities and show that mixing is achieved in a particularly controllable and fast way. The mixing quality is determined as a function of system parameters: SAW power, volume flux and fluid viscosity. Exploring the parameter space of mixing provides a practical guide for acoustic mixing in microchannels and allows for adopting conditions to different solvents, as e.g., required for the generation of nanoscale particles from alcoholic phases. We exemplarily demonstrate the potential of SAW based continuous flow mixing for the production of therapeutic nucleic acid nanoparticles assembled from polymer and lipid solutions.
Automated mixing of fluids with control over mixing parameters is of highest importance for reproducible production and chemical synthesis processes. We here introduce Surface Acoustic Waves (SAW) induced mixing of µL droplets for tailorable nanoparticle (NP) formation. Nucleic acid therapeutics represent extremely potent and innovative approaches to a variety of medical challenges, such as the treatment of cancer and genetic diseases. In this study, we apply this method to produce nucleic acid polymer complexes. Fusing two droplets containing either pDNA or cationic polymers leads to the formation of well-defined polyplexes. We show that droplet size and incubation time do not influence the desired particle characteristics significantly. However, the resulting nanoparticle diameter strongly depends on the SAW power level and educt concentrations, which indicates a kinetically controlled assembly process, while the particle shape is largely unaffected. Applying our novel technique to the formation of three-component-NP, we find that the choice of the mixing order can be used to decrease NP size even further. To address the kinetic interplay between mixing and particle growth, we apply our technique to homogenous mixing at high salt concentrations followed by a subsequent dilution step. Finally, by comparing various hand-and SAW-mixed polyplexes, we demonstrate significant differences in size while the cytotoxicity and in vitro efficacy remain roughly the same.
Invasion is strongly influenced by the mechanical properties of the extracellular matrix. Here, we use microfluidics to align fibers of a collagen matrix and study the influence of fiber orientation on invasion from a cancer cell spheroid. The microfluidic setup allows for highly oriented collagen fibers of tangential and radial orientation with respect to the spheroid, which can be described by finite element simulations. In invasion experiments, we observe a strong bias of invasion towards radial as compared to tangential fiber orientation. Simulations of the invasive behavior with a Brownian diffusion model suggest complete blockage of migration perpendicularly to fibers allowing for migration exclusively along fibers. This slows invasion toward areas with tangentially oriented fibers down, but does not prevent it.
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