# Synthesis of Hydrogel-Based Microgels and Nanogels Toward Therapeutic and Biomedical Applications
## 4 Paradigm Shift: Bulk Hydrogels to Hydrogel Micro/Nanoparticles
### Hydrogel Nanoparticle Synthesis
#### 4.3.1 Microfluidics-Assisted Polymerization  
The most conventional bottom-up approach to produce nanogels is the polymerization process, which can be coupled with a droplet-based system to constrain the reaction to a finite volume and to allow more uniform and rapid thermodynamic control. The microfluidic system offers an efficient strategy to realize this reaction environment, by formulating extremely small and uniformly sized droplets surrounded by a chemically inert fluid [216, 217]. In this microfluidic system, immiscible fluids flow through microchannels, where droplet generation is governed by hydrodynamic focusing and droplet breakup at flow junctions, and the produced droplets serve as a microreactor for nanogel formation, stabilized by subsequent crosslinking or polymerization processes such as ATRP or RAFT [58; 122; 237]. The microscopic dimension of the microchannel facilitates precise control over droplet size and polymerization reaction kinetics.  
Controlled polymerization is a fundamental process that enables the synthesis of nanogels, and it provides a controllability over molecular weight distribution, functional groups, and stimuli-responsive behavior [124; 165]. Approaches to forming nanogels via polymerization can be categorized into dispersion polymerization and precipitation polymerization. Dispersion polymerization occurs in a homogeneous solvent system where a monomer (precursor) and initiator are soluble at the beginning of the reaction. As polymerization progresses, the growing polymer chain becomes less soluble and begins to phase separate, which can be illustrated as the appearance of a small stabilized solid-like phase rich in polymer chains. With the aid of surfactants or ligands, this process results in the dispersion of spherical particles. The size of the resulting particle can be controlled by the number of monomers and reaction temperature and could reach sub-microns in diameter [124; 164]. Precipitation polymerization also begins with a similar system, but generally in the absence of a stabilizer to induce precipitation. Once the polymeric solid matter precipitates, polymerization continues on the surface and leads to particle growth [122; 238]. Comparing two approaches, dispersion polymerization generally produces larger-sized polymeric particles but with better size uniformity and scalability. The stability of the solid-rich phase also benefits the stable encapsulation of drug particles. Precipitation polymerization requires a simpler system and could synthesize smaller particles at the scale of tens of nanometers, but size controllability is largely affected by the nucleation mechanism, which is more difficult to control.  
Controlled polymerization methods such as ATPR and RAFT are another imperative factor in nanogel synthesis, which offer strategies to control the kinetics of nucleation and polymerization [164]. ATRP employs a transition metal catalyst to manipulate polymer growth, ensuring a controlled polymerization rate and narrow molecular weight distribution. RAFT polymerization leverages chain transfer agents to regulate how monomers are incorporated into growing polymeric chains, enabling the synthesis of nanoscale hydrogel particles as well as copolymerization with other precursors [122; 123; 124].