Crosslinking Strategies for the Microfluidic Production of Microgels

Abstract

This article provides a systematic review of the crosslinking strategies used to produce microgel particles in microfluidic chips. Various ionic crosslinking methods for the gelation of charged polymers are discussed, including external gelation via crosslinkers dissolved or dispersed in the oil phase; internal gelation methods using crosslinkers added to the dispersed phase in their non-active forms, such as chelating agents, photo-acid generators, sparingly soluble or slowly hydrolyzing compounds, and methods involving competitive ligand exchange; rapid mixing of polymer and crosslinking streams; and merging polymer and crosslinker droplets. Covalent crosslinking methods using enzymatic oxidation of modified biopolymers, photo-polymerization of crosslinkable monomers or polymers, and thiol-ene “click” reactions are also discussed, as well as methods based on the sol−gel transitions of stimuli responsive polymers triggered by pH or temperature change. In addition to homogeneous microgel particles, the production of structurally heterogeneous particles such as composite hydrogel particles entrapping droplet interface bilayers, core−shell particles, organoids, and Janus particles are also discussed. Microfluidics offers the ability to precisely tune the chemical composition, size, shape, surface morphology, and internal structure of microgels by bringing multiple fluid streams in contact in a highly controlled fashion using versatile channel geometries and flow configurations, and allowing for controlled crosslinking.

Cellulose through the Lens of Microfluidics: A Review

“…The scheme on the left makes microbeads using a T-section design, whereas the diagram on the right is for flow focusing for production of Janus particles. Reproduced with permissions from [267][268][269][270].…”

Microfluidic Particle Reactors: From Interface Characteristics to Cells and Drugs Related Biomedical Applications

“…Correspondingly, chemical methods suggest inducing polymerization through the chemical reaction of photopolymer [71,72] or crosslinking agent. [11,73] To summarize, the intrinsic mechanism of the chemical polymerization methods from emulsions into MPRs is that the monomer molecules polymerize to form an insoluble gel polymer with a 3D network structure. In other words, photocurable monomers and radical initiator or crosslinking agents are initially added to the dispersed and continuous phases of emulsion templates separately; then, the polymerization is confined within the emulsions when the radical initiator or one of the crosslinking agents diffuses into the dispersed phase.…”

“…As a result, a series of performances possessed by the materials can significantly improve the inherent interface characteristics of the MPRs under a combination of the mentioned advanced materials. [11][12][13][14][15][16] Overall, researchers have stressed the improvement of the development process of interface characteristics and functions (such as substance encapsulation and controlled release) by providing novel technical innovations in every aspect to support biomedical clinical applications related to cells and drugs. Recently, the types, preparation methods, and biomedical applications of MPRs have been systematically presented in several excellent reviews.…”

Microfluidic Formulation of Topological Hydrogels for Microtissue Engineering

“…In particular, the composition of the matrix can be engineered to locally promote or suppress cell–matrix interaction and thus control morphology of the ensuing microtissues. In terms of applications, the recent advancements in hydrogel microfabrication methods − have opened new perspectives in regenerative medicine, , personalized drug testing, − as well as in basic cell- and tissue physiology research, , including cancer research. − …”

“…In this review, we focus on the most recent developments in microfluidics-assisted formulation of biomaterials, in particular on those with nontrivial internal architecture, typically consisting of multiple distinct compartments. ,− ,, We use the term “microfluidics” to describe a set of techniques aimed at developing of high-level of control over tiny liquid volumes, typically nano- or even picoliter volumes, at submillimeter length scale. In particular, microfluidics can be used to disperse hydrogel precursor solutions into monodisperse droplets or extrude them into stable jets, which subsequently solidify, either spontaneously or via externally triggered cross-linking reaction, into hydrogel microparticles, ,,,,,− microfibers, − or more general “microgels”. The laminar (nonturbulent) flow conditions associated with small dimensions of the microchannels lead to reproducibility of droplet and jet morphologies as well as facilitate precise manipulation of the microscopic hydrogel liquid compartments, e.g., their on-chip merging or splitting .…”