ADVANCED BATCH AND IN-FLOW SYNTHESES OF POLYMERIC MICRO AND NANO PARTICLES FOR DRUG DELIVERY AND CELL ENCAPSULATION

The present work introduces innovative strategies in the synthesis and application of nanomaterials and microfluidic technologies for drug delivery and single-cell encapsulation. The main goal is to address the critical limitations of conventional methodologies, including poor reproducibility, limited scalability, and restricted material design. In recent years, nanogels (NGs) are emerging as a promising class of nanomaterial thanks to their unique properties, such as swelling, high drug loading, and good biocompatibility. To overcome the constrains of traditional NGs syntheses, a novel Mixed Emulsion/Evaporation Technique (MEET) and advanced microfluidic platforms, equipped with pneumatic actuation, were employed for the synthesis of hyaluronic acid – linear polyethyleneimine (HA-LPEI) NGs. MEET method overcomes the requirements of hydrophilic/hydrophobic polymer system in traditional emulsification/evaporation processes. The resulting NGs exhibited remarkable stability and controlled drug release. Moreover, folate surface functionalization was also introduced to further enhance targeting specificity towards tumor cells overexpressing folate receptors. In parallel, droplet-based microfluidic chip equipped with pneumatic micro-actuation allows the fine manipulation NG properties, such as size, monodispersity, and drug release kinetics. Microfluidically synthesized NGs showed unparalleled cell internalization and therapeutic efficacy, especially when compared with their bulk counterpart. To further explore the potentiality of these systems, a process optimization using Response Surface Methodology (RSM) was conducted and the developed empirical model allowed the prediction and control of NG physicochemical and biological properties as a function of synthesis parameters, including flow rate ratio and molar ratio. Additionally, a comparative analysis of two microfluidic geometries—flow-focusing junction (FFJ) and T-junction (TJ)—for alginate beads generation revealed the superior performance of the FFJ system. The FFJ device achieved higher production frequencies, reduced polydispersity, and enhanced bead circularity. Altogether, these performances strengthened the FFJ application as an ideal platform for single-cell encapsulation. The good viability of SKOV3 cells after the encapsulation process validates the applicability and stability of the alginate microbead system for up to seven days. Overall, this work proposes novel strategies in the design and functionalization of nanomaterials for drug delivery and reveals the promising application of microfluidic platforms for cell encapsulation purposes. These findings fulfill existing gaps in material synthesis and biomedical engineering, highlighting the promising application of microfluidics for future clinical translation in nanomedicine and personalized medicine.