Mild formation of core–shell hydrogel microcapsules for cell encapsulation

Internal gelation has been an important sol-gel route for the preparation of spherical microgel for drug delivery, cell therapy, or tissue regeneration. Despite high homogeneity and permeability, the internal gelated microgels often result in weak mechanical stability, unregular interface morphology and low cell survival rate. In this work, we have extensively improved the existing internal gelation approach and core–shell hydrogel microcapsules (200–600 μm) with a smooth surface, high mechanical stability and cell survival rate, are successfully prepared by using internal gelation. A coaxial flow-focusing capillary-assembled microfluidic device was developed for the gelation. Rapid gelling behavior of alginate in the internal gelation makes it suitable for producing well-defined and homogenous alginate hydrogel microstructures that serve as the shell of the microcapsules. 2-[4-(2-Hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (HEPES) was used in the shell stream during the internal gelation. Thus, a high concentration of acid in the oil solution can be used for better crosslinking the alginate while maintaining high cell viability. We further demonstrated that the gelation conditions in our approach were mild enough for encapsulating HepG2 cells and 3T3 fibroblasts without losing their viability and functionality in a co-culture environment.