*2.5. Stereocomplex Hydrogel*

A hydrogel is a network of cross-linked polymer chains. Hydrogels have been frequently used as scaffolds in tissue engineering and drug carriers and are known as the first biomaterials to be used in the human body. S.J. de Jong et al. reported that a stereocomplex hydrogel could be synthesized by mixing dextran-grafted L-lactate and D-lactate in an aqueous solution [47]. The stereocomplex hydrogel could encapsulate the IgG and lysozyme of the model protein, and the loaded contents were released by Fickian diffusion for six

days. Even after the release of sensitive proteins from the gel, the stereocomplex hydrogel played the role of a stable protein carrier as well as the maintenance of enzymatic activity. Subsequently, Hennink et al. fabricated a stereocomplex hydrogel by mixing dextran-L or D-lactate without organic solvents or crosslinking agents in an aqueous environment, as shown in Figure 11a [48]. Enantiomeric PLA oligomers grafted to dextran did not require artificial agents, because they were already crosslinked by stereocomplexation. Moreover, this stereocomplex hydrogel has the advantage of full biodegradability and clinical safety, because dextran is a non-toxic water-soluble polymer. Figure 11b shows the rheological properties of dex-(L)lactate and a mixture of dex-(L)lactate and dex-(D)lactate. A mixture of enantiomers exhibited a growth in the storage modulus (G') and a reduction of tan δ with time, whereas dex-(L)lactate showed no change in G' and tan δ with time. These results indicate that the hydrogel network was formed, and that the polymer had a more elastic property. This was presumed to be due to self-assembly between the chains of L-lactate and D-lactate via stereocomplexation. As shown in Figure 11c, the lysozyme was released from the dex-lactate hydrogel faster than IgG in the same carrier during the initial stage. The hydrogel with higher polydispersity (PDI) of the lactate graft showed faster release of the two model proteins compared to those with lower PDI. The results showed that all groups exhibited complete release of the loaded contents from the hydrogel after eight days and retained enzymatic activity. Hence, the sc-PLA hydrogel could encapsulate proteins and control release. It is potentially applicable to drug carriers with good biocompatibility and gelation behavior.

**Figure 11.** (**a**) Formation of stereocomplex hydrogel schematic via blending dextran-L or D-lactate without organic solvents or crosslinking agents. (**b**) Measurements of rheological properties of dex-(L)lactate and a mixture of dex-(L)lactate and dex-(D)lactate. Open circles and lines in the graph depict G' and tan δ, respectively [45], Copyright 2003. Reproduced with permission from Elsevier B.V. (**c**) Protein release profiles of lysozyme (indicated by dotted line in the graph) and IgG (indicated by solid line in the graph) from dex-lactate hydrogel exhibiting high (open symbols) and low (filled symbols) PDI. The measurement environment was at pH 7.0 and 37 ◦C. The data were plotted as mean values ±SD (*n* = 4) [47], Copyright 2001. Reproduced with permission from Elsevier Science B.V.

A strategy using in situ gelling systems has been used for the transformation of drug/polymer precursor complexes from solution after injection into the human body to gel form by physiological conditions of target tissues or artificial stimuli, such as pH or temperature change, UV irradiation, solvent exchange, catalytic ions, or molecules [49–51]. Generally, an in situ gelling hydrogel can be synthesized by various chemical reactions, including enzyme-catalyzed cross-linking, Schiff-base reaction, photo-induced polymerization, and Michael-type addition [52–55]. This drug delivery system can prevent adverse events in non-target tissues with improved availability of administration. Based on this strategy, sc-PLA-based hydrogels have the potential to improve the mechanical strength and durability and delay the degradation rate of the carrier induced by stereocomplexation in the future.
