# Synthesis of Hydrogel-Based Microgels and Nanogels Toward Therapeutic and Biomedical Applications
## 5 Therapeutic and Biomedical Applications of Micro- and Nano-Hydrogels
### Drug Delivery Across Blood-Brain Barrier  
The blood-brain barrier (BBB) poses the most challenging obstacle in therapeutic technologies for the central nervous system (CNS) [262]. This highly selective barrier, composed of tightly connected brain endothelial cells supported by astrocytes and pericytes, is the most critical defense for maintaining neural homeostasis, but it also restricts the passage of nearly 98% of small molecular drugs and almost all large-molecule-based therapeutics. This impermeability limits administrative options for neurological disorders, glioblastoma, neurodegenerative diseases, and CNS infections [149; 192; 202].  
Hydrogel materials are emerging as pivotal candidates for BBB-targeted DDS. Gelatin methacrylate, GelMA, is a photo-crosslinkable material derived from denatured collagen with excellent capacity to mimic the ECM [173]. Recent studies highlight the versatility of GelMA in applications requiring 3D scaffolds and drug encapsulation of both therapeutic agents and cells. PVA has also been increasingly utilized for the encapsulation of  
Figure 7: Hydrogel-based drug screening platforms. The materialistic benefits of hydrogel are especially suitable for 3D cell culture systems, allowing it to mimic the in vivo setting closer than the conventional 2D culture systems. (**a**) PEG/polysaccharide-based system, and (**b**) chemically modified PEG-based 3D culture system. (*,# \(p\) < 0.05). Licensed under CC BY 4.0, adapted from [176; 261].  
hydrophobic and hydrophilic drugs by leveraging the ease of chemical modification, which also enhances its compatibility with various biomolecules and targeting ligands [152].  
Recently, [PERSON] et al. synthesized chitosan (CS)-based nanogels functionalized with a tricarbocyanine (CNN) fluorescent probe to investigate its BBB traverse efficiency. Nanogel was ionically crosslinked using tripolyphophate, and the resulting particle sizes were measured as 273 and 435 nm, for CS and CS-CNN nanogels, respectively. Successful cellular uptake and endo/lysosomal escape were confirmed in neuroblastoma cells, and selective accumulation in mice brain was achieved within 2 h [194]. An in vitro BBB model made from GelMA-based hydrogel was recently reported by [PERSON] et al. This system is composed of a GelMA-astrocyte layer over endothelial cells to form a BBB-like physiological environment and is used to investigate the migration of triple-negative breast cancer cells, where up to 100% reduction was achieved at 20 uM of cisplatin concentration (Figure 8) [202]. Another advanced 3D BBB model was developed using PEG functionalized with RGD and IKVAVA peptides, by constructing an astrocyte-embedded hydrogel matrix and endothelial cells seeded on its surface. Barrier integrity was assessed using transendothelial electrical resistance (TEER) to estimate vascular permeability, and it was found to be closest to the in vivo BBB environment when the combination of RGD and IKVAV modification was applied. These findings emphasize the potential synergistic impacts of micro/nanogels and hydrogel-based platforms toward overcoming BBB and the discovery of advanced CNS therapeutic technologies [263].