Liquid–liquid two-phase systems for the production of porous hydrogels and hydrogel microspheres for biomedical applications: A tutorial review

Macroporous hydrogels may have direct applications in regenerative medicine as scaffolds to support tissue formation. Hydrogel microspheres may be used as drug-delivery vehicles or as building blocks to assemble modular scaffolds. A variety of techniques exist to produce macroporous hydrogels and hydrogel microspheres. A subset of these relies on liquid–liquid two-phase systems. Within this subset, vastly different types of polymerization processes are found. In this review, the history, terminology and classification of liquid–liquid two-phase polymerization and crosslinking are described. Instructive examples of hydrogel microsphere and macroporous scaffold formation by precipitation/dispersion, emulsion and suspension polymerizations are used to illustrate the nature of these processes. The role of the kinetics of phase separation in determining the morphology of scaffolds and microspheres is also delineated. Brief descriptions of miniemulsion, microemulsion polymerization and ionotropic gelation are also included.