Microfluidic Synthesis of Hyaluronic Acid Microgels in a Coaxial Flow Reactor

Microgels combine the strengths of hydrogels and microparticles. The multiple advantages of microgels, including control of drug release, excellent loading efficiency, high stability, and biocompatibility, make them an ideal vehicle for biotherapeutics. Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan which is used in many clinical applications, including formulation. Batch synthesis of cross‐linked HA microgels has been reported, but frequently leads to large polydisperse particles. In this study, we investigated the synthesis of divinyl sulfone cross‐linked HA microgels using a coaxial flow reactor to enable tuning of particle properties and continuous manufacture. The experimental parameters were optimized using Taguchi orthogonal arrays as a design of experiment (DoE) method. The DoE method allowed efficient exploration of reaction space, giving conditions which lead to hydrodynamic particle diameters from 230 to 1623 nm and polydispersity indices (PdIs) between 0.19 and 0.86. The DoE also allows extraction of effect sizes of the parameters on both particle size and PdI. It was found that all parameters included in the experiment design influenced the outcomes of the experiment, highlighting the advantages of taking this statistical approach to experiment design. From an initial DoE, a second orthogonal array was selected based on parameters that minimized size. This second array resulted in production of microgels with desirable properties for potential drug delivery applications (hydrodynamic diameter 261 nm, PdI 0.19) under the optimized conditions.