# Synthesis of Hydrogel-Based Microgels and Nanogels Toward Therapeutic and Biomedical Applications
## 2 Hydrogel Materials
### Synthetic Hydrogels  
#### 2.1.1 Acrylamide and Its Derivatives  
Acrylamide (AAm) and its derivatives are the most widely studied hydrogel precursors that can consecutively form hydrogels via chemical and physical mechanisms, including free radical polymerization as a commonly adapted chemical synthesis technique (Table 1). A precursor is a building block of a synthetic hydrogel and generally exhibits chemical functionalities which can be utilized to crosslink with another precursor in the presence of crosslinkers such as N,N'-methylenebisacrylamide [15; 19].  
AAm hydrogels exhibit high water absorptivity and sensitivity to their surrounding environments, such as pH, temperature, and chemical composition, which can trigger a physical or structural shift in gels, and they can stably retain a large amount of water within their network to undergo volumetric swelling without rupturing structural integrity. Common derivatives of AAm include polyacrylamide (PAAm), poly(N-isopropylacrylamide) (PNIPAm), poly(N-isopropylmethacrylate) (PNIPAm), and poly(N,N-diethylacrylamide) (PDEAm). Among those, PNIPAm, PNIPAM, and PDEAm are famously known as thermo-responsive polymers [15; 19; 20].  
One noticeable difference among the thermo-responsive AAm hydrogels is the classification of amine functional groups [21]. PDEAm has a tertiary amine group that can be protonated through the physiological or acidic condition, rendering the PDEAm hydrogels positively charged, and more broadly, sensitive. PNIPAm and PNIPAMm both have secondary amine groups and are generally known as neutral. Both hydrogels lack charged groups and could minimize the Coulombic interaction with cell membranes, thereby exhibiting relatively better biocompatibility and lower cytotoxicity [19; 22].  
The thermo-responsiveness of PDEAm, PNIPAm, and PNIPAMm are well represented by their lower critical solution temperature (LCST), a specific temperature at which the hydrogel transitions from a hydrophilic state to a hydrophobic state, often being described as a swollen state and collapsed state, respectively. This phenomenon causes the hydrogel dehydrates to be above their LCST, allowing the initially loaded solution within the hydrogel matrix to be \"squeezed out\". PNIPAm hydrogel has a lower critical solution temperature (LCST) of approximately 32 \({}^{\circ}\)C, making it particularly attractive to clinical applications, whereas PNIPAMm hydrogels exhibit a slightly higher LCST of around 40 \({}^{\circ}\)C due to the steric hindrance caused by the additional methyl group on its precursor as well as the significantly higher dehydration than PNIPAm above the LCST. PDEAm has been increasingly utilized in biomedical studies, owing to its LSCT similar to that of PNIPAm and its tertiary amide structure that serves as a hydrogen bonding acceptor [15; 23; 24]. However, the thermo-responsive characteristics of AAm hydrogels could suffer from thermal and mechanical hysteresis, ultimately limiting their applicability in repetitive uses. This side effect tends to be more pronounced in alkyl acrylamide hydrogels due to their high thermal sensitivity.