Production of Hydrophobic Microparticles at Safe-To-Inject Sizes for Intravascular Administration

Background/Objectives: Hydrophobic microparticles are one of the most versatile structures in drug delivery and tissue engineering. These constructs offer a protective environment for hydrophobic or water-sensitive compounds (e.g., drugs, peroxides), providing an optimal solution for numerous biomedical purposes, such as drug delivery or oxygen therapeutics. The intravascular administration of hydrophobic microparticles requires a safe-to-flow particle profile, which typically corresponds to a maximum size of 5 µm-the generally accepted diameter for the thinnest blood vessels in humans. However, the production of hydrophobic microparticles below this size range remains largely unexplored. In this work, we investigate the fabrication of hydrophobic microparticles at safe-to-inject and safe-to-flow sizes (<5 µm) for intravascular administration. Methods: Polycaprolactone microparticles (PCL MPs) are produced using a double-emulsification method with tip ultrasonication, for which various production parameters (PCL molecular weight, PCL concentration, type of stabilizer, and filtration) are optimized to obtain particles at sizes below 5 µm. Results: We achieve a PCL MP size distribution of 99.8% below this size limit, and prove that these particles can flow without obstruction through a microfluidic model emulating a thin human blood capillary (4.1 µm × 3.0 µm width × heigh). Conclusions: Overall, we demonstrate that hydrophobic microparticles can be fabricated at safe-to-flow sizes using a simple and scalable setup, paving the way towards their applicability as new intravascular injectables.