Water-in-Water Emulsion Based Synthesis of Hydrogel Nanospheres with Tunable Release Kinetics DERYA AYDIN 1 and SEDA KIZILEL 1,2 1.—Department of Chemical and Biological Engineering, Koc University, Sariyer, Istanbul 34450, Turkey. 2.—e-mail: skizilel@ku.edu.tr Poly(ethylene glycol) (PEG) micro/nanospheres have several unique advan- tages as polymer based drug delivery systems (DDS) such as tunable size, large surface area to volume ratio, and colloidal stability. Emulsification is one of the widely used methods for facile synthesis of micro/nanospheres. Two- phase aqueous system based on polymer–polymer immiscibility is a novel approach for preparation of water-in-water (w/w) emulsions. This method is promising for the synthesis of PEG micro/nanospheres for biological systems, since the emulsion is aqueous and do not require organic solvents or surfac- tants. Here, we report the synthesis of nano-scale PEG hydrogel particles using w/w emulsions using phase separation of dextran and PEG prepolymer. Dynamic light scattering (DLS) and scaning electron microscopy (SEM) re- sults demonstrated that nano-scale hydrogel spheres could be obtained with this approach. We investigated the release kinetics of a model drug, prega- balin (PGB) from PEG nanospheres and demonstrated the influence of poly- merization conditions on loading and release of the drug as well as the morphology and size distribution of PEG nanospheres. The experimental drug release data was fitted to a stretched exponential function which suggested high correlation with experimental results to predict half-time and drug re- lease rates from the model equation. The biocompatibility of nanospheres on human dermal fibroblasts using cell-survival assay suggested that PEG na- nospheres with altered concentrations are non-toxic, and can be considered for controlled drug/molecule delivery. INTRODUCTION Design and characterization of hydrogels have attracted significant attention in tissue engineering and pharmaceutical applications because of their tunable chemical and three-dimensional physical structure, good mechanical properties, high water content, and biocompatibility. 1–5 Poly(ethylene gly- col) (PEG) based micro/nano-scale hydrogels have been considered to overcome the problems associ- ated with macroscopic gels, such as small surface area-to-volume ratio, low encapsulation efficiency and longer response time to external stimuli. 6–8 PEG hydrogel particles still maintain desired char- acteristics of macroscopic PEG-based hydrogels, such as swelling capacity and biocompatibility, 9 furthermore they offer advantages such as a tun- able size from nanometers to micrometers, a large surface area for bioconjugation, and an interior network for incorporation and controlled release of molecules. 10–12 However, several limitations exist for the design and development of effective hydro- gel-based particles as drug delivery carriers for in vivo applications. 13 One important require- ment involves control over the dimension to be less than 200 nm in diameter, which can improve cellu- lar uptake of particles through cell membranes and reduce nanoparticle uptake through mononuclear phagocytic system. 14 This property can significantly increases the circulation time of particles in blood. 12,15 For the synthesis of PEG-based hydrogel micro/nanospheres, both solvent evaporation and emulsification methods have been widely used. However, organic solvent or surfactant is often needed in these techniques, and hence further use of obtained particles for biomedical applications is limited. 9,12,16,17 On the other hand, water-in-water (w/w) emulsions are based on polymer–polymer JOM DOI: 10.1007/s11837-016-1969-z Ó 2016 The Minerals, Metals & Materials Society