*2.3. Emulsion Blending*

Generally, sc-PLA is prepared by mixing two enantiomeric polymers in solution or in a melted state. However, these methods result in low stereocomplexation efficiency, loss of molecular weights, and original properties. The layer-by-layer (LbL) technique based on a Pickering emulsion template has been commonly used to fabricate nano- and microcapsules [30–34]. Despite its facilitated application to various fields, this approach has several concerns, including the requirement of inorganic solid multi-layer precursors, linkers, and templates, and inferior integrity and loading efficiency of a capsule [35–37]. To overcome these limitations, emulsion blending based on the droplet-in-droplet method has emerged as an alternative method to fabricate polymeric micro-carriers. Brzezi ´nski proposed a microfluidic approach based on a water-in-oil-in-water (W/O/W) double emulsion for the synthesis of hollow stereocomplex microcapsules [38]. In this study, 2- ureido-4[1H]-pyrimidinone (UPy)-functionalized PLA enantiomers formed stereocomplex

microcapsules at the water-chloroform interface via a one-step microfluidic self-assembly (Figure 5a). The capsule could reversibly control the assembly and disassembly to the supramolecular functionality of the interfacial assembly, unlike other microcarriers. This enables the capsule to freely adjust the stiffness and permeability of its shell and drug release. Figure 5b shows the morphological and structural reorganization of the sc-PLA microparticles induced by the W/O/W double emulsion. In this observation, microdroplets with a mean diameter of approximately 260 μm appear to have a high monodispersity and narrow size distribution. In particular, microcapsules were divided from the water phase by spontaneous dewetting after the oil droplets shrank. The inner oil droplet could maintain hollow stereocomplexed microcapsules induced at the interface between water and chloroform [39–41]. Finally, the sc-PLA-UPy microcapsules were precipitated with a mean diameter of approximately 160 μm. Stereocomplex crystallites were assumed to act as efficient nucleating agents and interfacial enhancers during this reaction [42].

**Figure 5.** (**a**) Schematic illustrations of UPy-PLA-OH chemical structure (**i**) and microfluidic device for induction of W/O/W emulsion droplets (**ii**). Optical microscope observations of monodisperse stereocomplexed drops (**iii**,**iv**), and UPy-PLA-OH unstable drops (**v**). Scale bars: 200 μm. (**b**) Change of structural arrangemen<sup>t</sup> of W/O/W double emulsion droplets. (**i**) sc-PLA-UPy double emulsion droplet, (**ii**,**iii**) separation of microcapsule in water phase, (**iv**–**vi**) shell solidification of the microcapsule induced by evaporation. Scale bars: 100 μm [38], Copyright 2017. Reproduced with permission from WILEY-VCH Verlag GmbH & Co.

Im et al. developed a novel strategy for blending two homopolymers of PLA in an oil-in-water (O/W) emulsion state [43]. This O/W emulsion blending method facilitated the rapid combination of solutions of PLLA and PDLA enantiomers with the addition of an emulsifier and mechanical stirring in a one-pot reactor (Figure 6a) [43]. During blending, stereocomplex crystals could be formed simultaneously with the diffusion of oil-phased PLLA and PDLA into water, emulsification induced by an emulsifier, and mechanical mixing. Unlike other phases, the emulsion phase could induce significantly rapid stereocomplexation by promoting supramolecular interactions derived from lower interfacial tension. Moreover, this method can significantly improve the time and cost, availability, and efficiency compared to conventional methods. As a result, sc-PLA particles fabricated by emulsion blending showed spherical morphology with an improved stereocomplexation efficiency of up to 99% (Figure 6b,c). Furthermore, fluorouracil (5-FU), a cancer drug, can be encapsulated into sc-PLA particles for stereocomplexation during O/W emulsion blending, as shown in Figure 7a. In the drug release profiling test for 5-FU, sc-PLA particles induced by emulsion blending loaded 13 wt% of 5-FU, and the drug was slowly released for eight days after the initial burst of drug release (Figure 7b). To the best of our knowledge, this is the first report on an O/W emulsion blending method for simultaneously inducing stereocomplexation and drug encapsulation in an emulsion state.

**Figure 6.** (**a**) Scheme for O/W emulsion blending approach for inducing sc-PLA. Inserted image exhibits sc-PLA particles prepared by emulsion blending. (**b**) SEM observations (X10000, left) and diameters (right) of sc-PLA particles prepared by various O/W emulsion blending named Emulsion 1-5. (**c**) Comparison of stereocomplexation efficiency (%) of sc-PLA particles prepared Emulsion 1-5. SCF: supercritical fluid technology [43], Copyright 2020. Reproduced with permission from the American Chemical Society.

**Figure 7.** (**a**) Schematic illustration of O/W emulsion blending for simultaneously inducing stereocomplexation and infiltration of 5-FU drugs. (**b**) Release profile of 5-FU from washed sc-PLA particles prepared by O/W emulsion blending over 12 days. Insert presents graph of released 5-FU concentration from neat, washed, and unwashed sc-PLA/5-FU specimens. Data are plotted as mean values ± standard deviation (SD) (*n* = 3) [43], Copyright 2020. Reproduced with permission from the American Chemical Society.
