# Synthesis of Hydrogel-Based Microgels and Nanogels Toward Therapeutic and Biomedical Applications
## 2 Hydrogel Materials
### Hybrid Hydrogels  
Hybridization is an advanced strategy to amplify and to combine desirable properties by creating a unique matrix of two or more hybrid materials. This approach could efficiently overcome the limitations of individual materials, such as the insufficient mechanical strength of natural hydrogels and the lack of bioactivity of synthetic hydrogels, as well as offer enhanced functionalities for complex biomedical applications. Hybrid hydrogel is an extremely diverse category and could not be simply classified without overlooking the critical perspective of each case; however, there are resemblances in their experimental approaches which include the interpenetrating polymer network (IPN), blending, copolymerization, and layer-by-layer assembly (Figure 2). IPNs generally involve two or more polymeric materials that are physically entangled without covalent bonds between each other [115]. This approach is known to be highly efficient for enhancing mechanical strength, swelling behavior and stability, and stimuli responsiveness. Compared to blending, IPN is often described as an interwoven network of two or more polymers that retains individual properties and functions synergistically [41, 116, 117]. Blending is a more straightforward strategy that combines natural hydrogel materials like chitosan or alginate with synthetic hydrogels such as polyacrylamide or polyurethane [18, 59, 118]. Blending is often used to describe a homogeneous mixture of two or more hydrogel materials that does not necessarily involve chain entanglement, with a primary aim to balance the advantages of each component such as mechanical stability or bioactivity [118, 119, 120]. Copolymerization is a type of polymerization reaction that involves two or more types of monomers forming a chain composed of more than one monomer. It is often applied to synthetic hydrogels, where different types of monomers are sequentially fed during the controlled radical polymerization process like atom transfer radical polymerization (ATRP) or reversible addition fragmentation chain transfer (RAFT) [121, 122]. Notable differences in copolymerization from other approaches are the precise control over the resulting polymer in the molecular scale, including composition, molecular weight, statistical uniformity, and sequence of monomers, which are especially crucial in nanoscale hydrogel composites [123, 124, 125, 126, 127]. Layer-by-layer assembly (LbL) is a repetitive process that yields a sequentially multilayered composite of varying materials [128, 129, 130]. The most common example is an alternating deposition of oppositely charged polymeric materials, and each layer is stably  
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incorporated with previously applied layers via electrostatic attraction. Another approach has made noticeable advancements by adapting additive manufacturing technologies. Hydrogels are increasingly adapted into 3D printings, owing to their unique characteristics, including dynamic sol-gel transition, tunable viscosity, and selective gelation [130]. One major advantage of the LbL assembly is the precise spatial control over the hydrogel by incorporating a certain group of materials within the deposition sequence, allowing us to design a multilayer hybrid for a specific application such as drug release or tissue scaffolding [119; 120; 131]. Nanocomposite formation incorporates various nanomaterials such as graphene oxide, silica nanoparticles, or other inorganic nanocrystals with hydrogel material to improve mechanical properties and thermal stability, and to implant unique functionalities [56; 132]. Nanomaterials can be either dispersed into precursors of hydrogel or directly grafted onto polymeric chains [54; 118; 133; 134; 135; 136]. Though the aims of hybridization vary from case to case, major considerations must be made in designing hybrid hydrogels.