# Synthesis of Hydrogel-Based Microgels and Nanogels Toward Therapeutic and Biomedical Applications
## 2 Hydrogel Materials
### Synthetic Hydrogels
#### 2.1.2 Polyethylene Glycol and Its Derivatives  
Poly(ethylene glycol) diacrylate (PEGDA) hydrogel is represented by its promising potential in biomedical and clinical applications, including biocompatibility, flexibility, high water permeability, strong tissue adhesion, and intrinsically low cytotoxicity [25; 26; 27]. Owing to these advantages, PEGDA hydrogels have been increasingly adapted in tissue engineering, drug delivery, and bio-adhesive applications. PEGDA precursors are commercially available at various molecular weights from two hundred and fifty to over a few thousand g/mol, allowing us to combine short- and long-chain precursors to tune crosslinking density, elasticity, mechanical strength, and cell viability [28; 29]. The molecular weight of the PEGDA precursor plays a significant role in determining its overall characteristics, for example, higher-molecular-weight PEGDA tends to form more stretchable hydrogels with higher tensile strength owing to longer chains between two acrylate end groups, but it has been reported that enhancing the mechanical strength of PEGDA hydrogels could result in decreased cell viability [30]. However, the cytotoxicity of PEGDA hydrogels is also affected by total precursor concentration and precursor composition, making its overall dependency highly non-linear and difficult to estimate. The reasoning for this complex trend is based on two separate hypotheses. One suggests that higher crosslinking density, caused by lower-molecular-weight PEGDAs, renders the pores of a hydrogel network smaller, limiting the mass transfer rate of nutrients and growth factors as well as suppressing cell motility, hence providing opposing effects to cell proliferation and viability [25,31,32]. Another hypothesis is that the precursor with longer chains allows higher chain mobility and increased gel elasticity, providing a suitable environment for the seeded cells, whereas the precursor with shorter chains could adversely affect cells more severely than that with longer chains. For residual precursors, smaller molecules exhibit a faster diffusion rate than larger molecules within a gel matrix, while its acrylate end groups remain active to affect nearby cells [30,33]. In the aspects of hydrophilicity and swelling, PEG itself exhibits high water solubility, but its oligomeric or polymeric chain length directly affects the hydrophilicity and water absorption capacity of the resulting hydrogels. PEGDA hydrogels made from lower-molecular-weight PEGDA, and hence having a higher crosslinking density, are less hydrophilic and more mechanically robust than the hydrogels synthesized from higher-molecular-weight PEGDA. This phenomenon restricts water uptake and swelling and directly impacts the rate of biodegradation which makes it suitable for clinical long-term implants and stress-bearing scaffolds. Conventionally, PEGDA hydrogel is formed via UV-induced photopolymerization by taking advantage of its relatively high solubility to commercially available photoinitiators (Table 1). When combined with an adequate photoinitiator, such as Irgacure 2959 or 2-hydroxy-2-methylpropiphenone (HMP), and a light source, the precursors could readily form a crosslinking network without any need for heat or electrical bias, which allows light-controlled synthesis as well as tunable crosslinking density and mechanical stability [3,31,34]. Poly(ethylene glycol) dimethacrylate (PEGDMA) is another derivative of PEG-based hydrogel that has minimal toxicity and is modifiable to be bio-inert [35]. It also exhibits similar reaction characteristics to PEGDA, which allows facile control over its crosslinking density, water retention, and mechanical stability. In the aspect of biomedical applications, this controllability enables PEGDA hydrogels to sustain or to tailor the release dynamics of bioactive molecules or to resemble the physiochemical properties of an extracellular matrix to aid the interactions at the vascular interfaces or bond scaffolds [31,34].