# Synthesis of Hydrogel-Based Microgels and Nanogels Toward Therapeutic and Biomedical Applications
## 4 Paradigm Shift: Bulk Hydrogels to Hydrogel Micro/Nanoparticles  
Hydrogels, widely utilized in bioengineering applications like scaffolds and coatings, have recently seen transformative advances through the miniaturizations of a bulk system into the micro- and nanoscale, known as microgels and nanogels. This physical transition offers new unique properties like dynamic responsiveness along with the benefits of the reduced size scale, opening new potential regarding hydrogel-based biomedical technologies. Miniaturizing bulk hydrogels into nanogels introduces a series of distinctive attributes including increased surface area, rapid responsive kinetics, enhanced drug delivery, and mechanical flexibility [84, 182, 183]. The surface-to-volume ratio drastically increases as the size of the system reduces to nanoscale, which facilitates an extensive surface for additional functionalization. This increased ratio can directly affect the overall characteristics of the hydrogel because the surface-driven properties become more pronounced than the volume-driven properties as the surface area increases. Additionally, transport phenomena of heat and mass generally occur at faster rates in a smaller-scale system. For example, a shorter diffusion length enables faster swelling and deswelling, or drug release, when it is triggered via pH shift or temperature shift. Thereby, miniaturization enables rapid and reversible responses to stimuli such as pH, temperature, or light, allowing more precisely controllable hydrogel systems [5, 8, 10, 184]. For drug delivery systems, nanoparticles exhibit a unique passive tumor-targeting phenomenon called the enhanced permeability and retention (EPR) effect [10, 102, 184, 185]. This phenomenon is caused by the formation of blood vessels with high vascular permeability in the tumor microenvironment. Abnormal angiogenesis is not directly related to the onset of a tumor, but it is critical for the fate of the tumor since it requires higher vessel density as its size exceeds a few millimeters. The EPR effect describes how nanoparticles below 200 nm in size show selective accumulation within and near the tumor sites, while the same particles still cannot efficiently pass through the endothelial barriers of normal vessels [184, 186, 187, 188, 189]. This property offers a distinct advantage over bulk hydrogels, which often lack directive tumor targeting and exhibit slower drug release kinetics due to their larger size and slower responsiveness [190; 191]. Thin-film hydrogels, a unique class of hydrogel systems, offer a distinctive approach bridging the gap between bulk scale hydrogels and micro/nanogels. Thin-film hydrogels are typically micrometers thin and present a highly adaptable platform that can serve as a coating or membrane [191]. Macroscopic film systems can contribute to the overall mechanical stability or provide a protective interface, while nanoscale thin films can leverage selective permeability and rapid stimuli responsiveness, making them suitable for biosensors or drug delivery patches. However, thin-film hydrogels remain fundamentally different from microgels and nanogels despite their versatility. Thin films lack the discrete and particulate nature of micro/nanogels, limiting their application to superficial interfaces, such as skin or dressing, or hard interfaces. However, miniaturized hydrogel systems like microgels and nanogels also exhibit inherent disadvantages compared to their bulk counterparts. One major limitation is reduced mechanical stability, which restricts their use in load-bearing applications or high-shear environments [15; 136]. Also, the fabrication of microgel and nanogel often involves complex and lengthy processes, requiring additional equipment or precise process control. The uncontrolled synthesis of these systems may lead to reduced retention at the target site or premature clearance by the immune system. Another significant challenge arises from the biocompatibility and cytotoxic effect associated with functionalized hydrogels [69; 171].