Design and Synthesis of Fluorosurfactants for Microfluidic Droplet-Based Bioapplications

Surfactants are central to droplet-based microfluidics, where they stabilize immiscible interfaces, prevent coalescence, and enable precise control of discrete fluid volumes for biological and chemical applications. Recent efforts in fluorosurfactant design have emphasized how variations in hydrophilic head groups, fluorinated tail architecture, and synthesis strategies determine performance in droplet systems. This review surveys advances from conventional polyethylene glycol (PEG)-perfluoropolyether (PFPE) architectures to emerging alternatives with nonionic polar head groups, highlighting those with the greatest potential to advance the field. Particular attention is given to reversible addition-fragmentation chain transfer (RAFT) polymerization, which has revolutionized fluorosurfactant development by enabling precise molecular control and tunable properties. This has allowed the integration of responsive functionalities, including temperature-sensitive <i>N</i>-isopropylacrylamide (NIPAM), pH-responsive 2-(dimethylamino)-ethyl acrylate (DMAEA), and zwitterionic monomers, thereby greatly expanding functional versatility. Such innovations improve droplet stability, suppress molecular exchange, and enhance biocompatibility under challenging experimental conditions. These advanced fluorosurfactants demonstrate exceptional utility across a spectrum of biological applications, including high-throughput screening, droplet digital PCR, single-cell genomics, cell encapsulation, and three-dimensional culture systems. Collectively, they establish a foundation for next-generation microfluidic technologies that demand robust compartmentalization with minimal biological interference.