Mild formation of core–shell hydrogel microcapsules for cell encapsulation

Abstract

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.

Lab-on-Chip Microsystems for Ex Vivo Network of Neurons Studies: A Review

“…(A) A blood–brain barrier model by endothelial cells, pericytes, and astrocytes (HBMEC: human brain microvascular endothelial cells, HBVP: human brain vascular pericytes; HA: human astrocytes) ( Ahn et al, 2020 ). (B) A coaxial flow-focusing capillary-assembled microfluidic device to fabricate spherical hydrogel beads with cells in it ( Liu et al, 2020 ).…”

“…Other materials like fibrous and solid porous are also popular for cell culture use for various applications ( Hayman et al, 2005 ; Cao et al, 2009 ). Liu et al proposed a coaxial flow-focusing capillary-assembled microfluidic device to fabricate spherical hydrogel beads with cells in them, as shown in Figure 2B ( Liu et al, 2020 ). Alginate, one kind of hydrogel that could be solidified with calcium iron, was used as the shell of the sphere.…”

Crosslinking Strategies for the Microfluidic Production of Microgels

“…Hollow microgel capsules can be generated by the internal gelation of core−shell droplets within an O/W/O double emulsion [ 116 , 120 ]. In this approach, usually Ca-EDTA or CaCO 3 is added to the alginate solution in the middle phase, and crosslinking is initiated on-chip by organic acid dissolved in the outer oil phase [ 120 ] or off-chip by collecting the formed double emulsion droplets in an acidified oil phase [ 116 ]. Alternatively, a photo-acid generator (PAG) can be added to the middle phase to trigger crosslinking by UV light.…”

Crosslinking Strategies for Microfluidic Production of Microgels

“…In a similar way, core-shell beads consisting of a mixture of Matrigel, collagen and alginate in the core (solidified by temperature control) and alginate in the shell (solidfied by internal gelation using CaCO3 and acetic acid) were produced via a W/W/O template emulsion [113]. Hollow microgel capsules can be generated by internal gelation of core/shell droplets within O/W/O double emulsion [111,115]. In this approach, usually Ca-EDTA or CaCO3 is added to the alginate solution in the middle phase and crosslinking is initiated on-chip by organic acid dissolved in the outer oil phase [115] or off-chip by collecting the formed double emulsion droplets in an acidified oil phase [111].…”

“…Hollow microgel capsules can be generated by internal gelation of core/shell droplets within O/W/O double emulsion [111,115]. In this approach, usually Ca-EDTA or CaCO3 is added to the alginate solution in the middle phase and crosslinking is initiated on-chip by organic acid dissolved in the outer oil phase [115] or off-chip by collecting the formed double emulsion droplets in an acidified oil phase [111]. Alternatively, a photo-acid generator (PAG) can be added to the middle phase to trigger crosslinking by UV light.…”