# Biodegradable Polymeric Architectures via Reversible Deactivation Radical Polymerizations
## 2 Biodegradable Polymeric Architectures
### Hydrogels and Nanogels  
#### 2.3.1 Hydrogels  
Hydrogels are optimal materials for tissue engineering scaffolds due to their tissue-like mechanical compliance and mass transfer properties. However, many hydrogels that have been widely used in medical science are not biodegradable, thus cannot be easily and quickly cleared out of the body. Therefore, using biocompatible and biodegradable co-polymers for fabricating hydrogels is much desired. [PERSON] and coworkers successfully prepared cross-linked nanogels of biodegradable poly(2-hydroxyethyl methacrylate) (PHEMA) as engineered tissue constructs using ATRP technique and an enzyme degradable cross-linking agent, polycaprolactone (PCL) and a degradable macro-initiator that also contained oligomeric PCL [37].  
The hydrogel of nanostructured hyaluronic acid has also be generated in situ by [PERSON]'s group under physiological conditions (pH 7.4, 37 \({}^{\circ}\)C) by a combination of ATRP and Michael-type addition reaction using biodegradable nanogel precursors, 2-hydroxyethyl p(OEO300 MA-_co_-methacrylate) (POEO300 MA-_co_-PHEMA) [82]. RAFT agent in the form of \"RAFT gel\" has also been prepared by [PERSON]'s group via chemoselective polycondensations of a dicarboxylic acid containing a mercapto group and further used for the polymerization of methyl methacrylate to afford polyester containing biodegradable hydrogels [83]. It is well known that the synthetic poly(amino acid)s that have polypeptide backbone can be degraded in biological environments by enzymes such as proteinases and peptidases. [PERSON] et al. successfully prepared such cross-linked biodegradable hydrogels of a series of polymer architectures with the same polypeptide backbone via ring opening polymerization. They also found the enzyme-catalyzed hydrolysis can be controlled through copolymerization and/or side-chain modifications [38]. A combination of anionic and RAFT polymerization was used to synthesize an triblock polymer poly-[(propylesulfide)-_b_-(_N_,_N_-dimethylacrylamide)-_b_-(_N_-isopropylacrylamide)] (PPS-_b_-PDMA-_b_-PNIPAAM) that forms physically cross-linked hydrogels when transitioned from mechanisms for reactive oxygen species (ROS) triggered degradation and drug release. At ambient temperature, PPS-_b_-PDMA-_b_-PNIPAAM assembled into 66 \(\pm\) 32 nm micelles comprising a hydrophobic PPS core and PNIPAAM on the outer corona. The PPS-_b_-PDMA-_b_-PNIPAAM micelles were preloaded with the model drug Nile red and the resulting hydrogels demonstrated ROS-dependent drug release. The hydrogels were cyto-compatible in vitro and demonstrated to have utility for cell  
Figure 6: **(a)** (Left) Controlled radical cross-linking copolymerization through in situ DE-ATRP, followed by a post-functionalization process; and (Right) graphical representation of structures with different degrees of branching. The efficacy of functionalization depends on the content of the pendent vinyl groups; **(b)** Graphical representation of the degradation of structures with different degrees of branching. Copyright 2014, Wiley-VCH.  
encapsulation and delivery. These hydrogels also possessed inherent cell-protective properties and reduced ROS-mediated cellular death in vitro. Subcutaneously injected PPS-\(b\)-PDMA-\(b\)-PNIPAAM polymer solutions formed stable hydrogels that sustained local release of the model drug Nile red for 14 days in vivo. These collective data demonstrate the potential use of PPS-\(b\)-PDMA-\(b\)-PNIPAAM as an injectable, cyto-protective hydrogel that overcomes conventional PNIPAAM hydrogel limitations such as synoresis, lack of degradability, lack of inherent drug loading and environmentally responsive release mechanisms (Figure 7) [84].