(738e) 3D Hydrodynamic Focusing for Confined Precipitation of Nanoparticles within Microfluidic Channels

Hydrodynamic focusing in a microfluidic channel provides homogeneous reaction conditions that allow for various synthesis applications including polymeric nanoparticle synthesis by nanoprecipitation. Although microfluidic platforms have advantages of rapid mixing and controlled precipitation resulting in homogeneous particles, control of aggregation is a nontrivial issue since polymer particles tend to stick to channel walls and rapidly agglomerate inside, blocking the entire channel. Polymer aggregation can be avoided by 3D hydrodynamic focusing where the polymer stream is constrained both horizontally and vertically. We present the simplest design for 3D hydrodynamic focusing as the means of such absolute isolation (Fig). It is constructed on a single PDMS layer consisting of three sequential inlets to a conventional 2D hydrodynamic focusing system. The sample flow is first vertically focused by two vertical sheath flows and then horizontally squeezed into a narrow stream flowing in the outlet channel. The influence of the total flow rate, the flow rate ratio, and the sample concentration was investigated by mathematical modeling, finite element simulations, and polymeric nanoparticle synthesis experiments. Computer simulations showed that the size and position of inlet holes play a critical role in determining the shape of hydrodynamic focusing in the channel. When the inlet hole size is comparable to the channel width, the sample stream is successfully constrained in a horizontal band. In case of such complete vertical lamination, two-dimensional analytical models become sufficiently accurate. One can also simply increase the channel height to achieve similar focusing results. Molecules in the vertically focused stream gradually diffuse into both sheath streams, eventually reaching the top and bottom walls. Simulated bottom wall concentrations perfectly match with the predicted values from two-dimensional mathematical modeling. The performance of 3D focusing was also confirmed experimentally. Poly(lactic-co-glycolic acid) (PLGA) particles are known to agglomerate rapidly by precipitation in water because they are amorphous and hydrophobic. Consequently, PLGA nanoparticles with diameters smaller than 80 nm were almost impossible to synthesize by conventional 2D hydrodynamic focusing. PLGA precipitation at the channel wall during 2D hydrodynamic focusing; but 3D hydrodynamic focusing can prevent this precipitation. Confocal micrographs show cross-sectional views with vertical focusing. Using 3D hydrodynamic focusing, we synthesized various polymeric nanoparticles that could neither be synthesized by 2D hydrodynamic focusing nor by bulk mixing in a conventional way. The sample stream containing polymer precursors in acetonitrile (ACN) first makes a vertically squeezed stream by two vertical ACN sheath streams. The vertically arranged stream then meets two horizontal sheath streams (water) flowing at higher flow rates. TEM images of PLGA-PEG nanoparticles obtained from PLGA27K-PEG5K at 10 mg/mL and PLGA45K-PEG5K at 30 mg/mL in ACN show that the average nanoparticle sizes are 33nm and 55nm, respectively. In conclusion, 3D hydrodynamic focusing enabled by simple inlet arrangement not only allows for robust and predictable synthesis of polymeric nanoparticles for precursors with different molecular weights and concentrations, but also yields smaller and monodisperse nanoparticles.