# Synthesis of Hydrogel-Based Microgels and Nanogels Toward Therapeutic and Biomedical Applications
## 4 Paradigm Shift: Bulk Hydrogels to Hydrogel Micro/Nanoparticles
### Hydrogel Microparticle Synthesis
#### 4.2.1 Microfluidic Emulsification  
Microfluidics is a class of fluid dynamics with an emphasis on microscale systems and has increasingly adapted into diverse fields, benefiting from the advances in microfabrication technologies. A microfluidic system allows precise control of one or more types of fluid flow and their fluid dynamic behaviors including mixing, phase separation, and flow profiles [216; 217; 218]. When two immiscible fluids are injected into a microfluidic system in the same direction, two fluids form an interphase along their primary flow direction. Depending on their flow rate difference, interfacial tension, or shear stress, one fluid could become disconnected (dispersed phase), which naturally takes a spherical form, while the other fluid surrounds it (continuous phase), forming a continuous flow of uniformly sized droplets [219]. The size of the droplets can be controlled by adjusting the same parameters, allowing the precision synthesis of droplets measuring from sub-micron to several millimeters. Microfluidic techniques leverage the precise control of droplet formation within the microchannel to create hydrogel microparticles (Figure 4). One significant advantage of microfluidic synthesis is the ability to produce monodisperse particles with highly controlled size and morphology, which is essential for precise dosing and uniform cellular responses. This precision also allows the fabrication of advanced microarchitectures including core-shell structures, Janus particles, and multi-compartmental designs [217; 218; 219; 220]. Emulsion, commonly referred to as droplets, is a minute volume of a fluid dispersed in another immiscible fluid phase, which is directly applicable by making a discrete phase  
Figure 4: Synthesis technologies of hydrogel micro- and nanoparticles (microgels and nanogels). Emulsification involves immiscible fluids, forming a discrete volume of hydrogel precursors that define the physical size of the microgel. The achievable size of emulsion varies by the types of emulsification technique, size of the system, etc. Electrospraying generally exhibits large reductions from the aerosol size to the resulting solid particles. Reproduced with permission from [221; 222; 223]. Licensed under CC BY 4.0, adapted from [224; 225]. for hydrogel materials and required additives to induce crosslinking. In this approach, a hydrogel microparticle is formed via a stepwise process, droplet formation, and hydrogel crosslinking, which can be modified to introduce drug molecules, buffer exchange, or purification by modifying microfluidic designs [182; 226]. For example, a microfluidic orifice is an effective design to formulate localized high-interfacial tension sites, pinching an initially continuous hydrogel solution to form droplets. Also, a complex microfluidic design can be realized via photolithography to combine a curved microchannel with a droplet generator [218]. In this design, a centripetal force exerted on a denser phase induces radially outward flow perpendicular to the primary flow direction, enabling the high throughput of hydrogel microparticle synthesis within a compact form factor device [219; 227]. One careful consideration that needs to be made for the microfluidic approach is the high operational pressure [182; 188]. For the simplest straight cylindrical microchannel, the flow dynamic behavior in this model is well described by the Hagen-Poiseuille equation. \[\Delta P=\frac{8\mu L_{c}Q}{\pi r_{c}^{4}}\]  
where \(\Delta P\) is the pressure drop, \(\mu\) is the viscosity of the fluid, \(Q\) is the volumetric flow rate, and \(L_{c}\) and \(r_{c}\) are the length and radius of the microchannel, respectively. As described in the equation above, narrowing down a microchannel incurs a steep increase in the pressure required to maintain the flow rate. A high-pressure operation poses practical challenges, including limited throughput and scalability.