Droplet-Based Microfluidic Synthesis of Hydrogel Microparticles via Click Chemistry-Based Cross-Linking for the Controlled Release of Proteins

Abstract

Hydrogel microparticles (HMPs) have been widely applied in biological, pharmacologic, and biomedical industries due to their versatility. Particle size is a paramount factor for controlling drug release profiles from HMPs. Conventional fabrication methods such as bulk emulsion, coacervation, and spray drying do not offer a precise size control and high reproducibility, which may compromise the utility of HMPs for controlled release. Here, we report a droplet-based microfluidic synthesis method for the precise fabrication of HMPs. Functionalized polysaccharides/protein fluid mixtures were emulsified into monodisperse droplets in light mineral oil using a flow-focusing device and well mixed in precursor droplets through a serpentine mixing channel before the solidification of HMPs. The homogenized precursor polymers cross-link in the droplets by catalyst-free Michael addition. As a demonstration of the controlled release of a model drug from the HMPs, fluorescein-labeled immunoglobulin G (F-IgG) and bevacizumab were encapsulated in the HMPs of different diameters for measuring its release dynamics over time. The release kinetics of F-IgG from the HMPs was shown to be controllable by altering the particle size while keeping other parameters unchanged. Around 70% of bevacizumab released from DX HMPs was functional. Both HA and DX HMPs showed no cytotoxicity in the HEK293 cell line. We anticipate that this approach could be used as a general method to fabricate HMPs made of hydrophilic polymers for the controlled release of biotherapeutics.