Design of Modular, 3D-Printed Millifluidic Mixers to Enable Sequential NanoPrecipitation (SNaP) for the Tunable Synthesis of Drug-Loaded Nanoparticles and Microparticles

Sequential NanoPrecipitation (SNaP) is a nascent controlled precipitation process for the tunable formation of polymeric particles for drug delivery and bioimaging. While SNaP utilizes the same self-assembly principles as one-step Flash NanoPrecipitation, SNaP is a two-step assembly process in which the particle core formation is initiated during a first mixing step followed by particle stabilization in a second mixing step. Current SNaP experimental set-ups use commercial millifluidic mixers connected in series, which have several limitations, including the inability to access short inter-mixer delay times (Td). A robust, 3D-printed, modular mixer design that enables access to short Td's (〈 25 ms) not previously accessible is reported. For the first time, it is demonstrated that decoupling the assembly steps improves control over particle size, expanding the attainable size range to include both nanoparticles and microparticles. It is empirically proven that inter-mixer Td is a key parameter for particle size control and that particle size scales with Td in agreement with Smoluchowski's model of diffusion-limited growth. The formation of particles ranging in size from 160 nm to 1.2 µm is shown. Finally, the applicability of the new mixers is established by encapsulating fluorophores and therapeutics into particles for the first time via SNaP.