A new strategy for the preparation of nanogels from commercially available monomers of bisepoxide and aliphatic polyetheramine has been developed. The nanogels are generated in a one-pot process through aggregation polymerization of an in situ formed thermal sensitive intermediate polymer in an additive-free and catalyst-free aqueous environment. Such a facile process allows easy size tuning of the gel particles from the nanometer to the micron scale, simply by adjusting the reactant concentration. The obtained nanogels demonstrated responsiveness to multiple biologically relevant stimuli, including temperature, pH, and oxidation. Nile red was encapsulated in the nanogels as a model hydrophobic drug. In vitro drug release studies showed stimuli-triggered release from the nanogels, suggesting the potential for controlled drug delivery.

Hybrid agarose hydrogels embedded with pH-responsive diblock copolymers micelles were developed to achieve functional hydrogels capable of stimulus-triggered drug release. Specifically, a well-defined poly(ethylene oxide) (PEO)-based diblock copolymer, PEO-bpoly(2-(N,N-diisopropylamino)ethyl methacrylate) (PEO113-b-PDPAEMA31, where the subscripts represent the degrees of polymerization of two blocks), was synthesized by atom transfer radical polymerization. PDPAEMA is a pH-responsive polymer with a pKa value of 6.3. The PEO113-b-PDPAEMA31 micelles were formed by a solvent-switching method, and their pH-dependent dissociation behavior was investigated by dynamic light scattering and fluorescence spectroscopy. Both studies indicated that the micelles were completely disassembled at pH = 6.40. The biocompatibility of PEO113-b-PDPAEMA31 micelles was demonstrated by in vitro primary cortical neural culture. Hybrid agarose hydrogels were made by cooling agarose solutions that contained various amounts of PEO113-b-PDPAEMA31 micelles at either 2 or 4 °C. Rheological measurements showed that the mechanical properties of gels were not significantly adversely affected by the incorporation of diblock copolymer micelles with a concentration as high as 5.0 mg/g. Using Nile Red as a model hydrophobic drug, its incorporation into the core of diblock copolymer micelles was demonstrated. Characterized by fluorescent spectroscopy, the release of Nile Red from the hybrid hydrogel was shown to be controllable by pH due to the responsiveness of the block copolymer micelles. Based on the prominent use of agarose gels as scaffolds for cell transplantation for neural repair, the hybrid hydrogels embedded with stimuli-responsive block copolymer micelles could allow the controlled delivery of hydrophobic neuroprotective agents to improve survival of transplanted cells in tune with signals from the surrounding pathological environment.

Synthetic materials such as silicon have been commonly used for neural interfacing applications but are intrinsically noninteractive with neurons. Here, a facile approach has been developed to integrate both chemical and topographical cues to impart neural permissiveness for such materials. The approach simply exploits the basic phenomenon of electrostatically driven adsorption of colloidal particles onto a solid material and applies it to a cationic hydrogel particle system that we have developed recently based on "click" reaction of epoxide and amine. The particle adsorption process can be tuned by varying the adsorption time and the concentration of the original colloidal suspension, both of which directly control the surface densities of the adsorbed hydrogel particles. Using the PC12 cell line and primary cortical neurons derived from chick embryo, we demonstrate that the particle-adsorbed surface readily supports robust cell adhesion and differentiation. Although the extent of neural permissiveness exhibited by such particle-adsorbed surface was comparable to the cationic polyethylenimine-coated control surface, the adsorbed hydrogel particles offer a unique reservoir function to the modified surface that is unparalleled by the control. The successful loading of hydrophobic dye of nile red to the surface adsorbed hydrogel particles indicates that the modified surface not only provides physical support of neurons, but also can be explored in the future to exert localized therapeutic actions favorable for neural interfacing.

A new monomer derivative of N‐vinyl‐2‐caprolactam (VCL), namely 3‐(tert‐butoxycarbonylmethyl)‐N‐vinyl‐2‐caprolactam (TBMVCL), was synthesized via nucleophilic substitution at the α‐carbon to the lactam carbonyl group. The monomer was copolymerized radically with VCL and the copolymer compositions were controlled through varying the molar feeding percentages of TBMVCL. The resulting copolymers exhibited temperature‐responsive properties in water, with cloud points decreasing from 33 °C to 13 °C when the TBMVCL composition increased from 2.2 mol % to 18.6 mol %. Removal of the tert‐butyl protecting groups via acid hydrolysis exposed the carboxyl groups, which conferred pH sensitivity to the thermoresponsive properties of the resulting deprotected copolymers. The cloud point was found to increase with the increase of solution pH from 2.0 to 7.4, due to the ionization of the carboxyl groups. The influence of pH was most drastic for the 18.6 mol % copolymer composition. Furthermore, the phase transition temperature of the deprotected copolymers was found to be dependent on the polymer solution concentration, exemplifying classical Flory–Huggins miscibility behavior. Comparison of responsiveness was also made with another type of carboxyl functionalized poly(N‐vinyl‐2‐caprolactam) copolymer reported in our prior study, to examine the influence of the chemical structure of the carboxyl substitution group. Finally, the deprotected copolymer was demonstrated to be biocompatible using a fibroblast cell culture. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 112–120

Micro/nanoscale hydrogel particles are of great interest for biomedical applications, such as carriers for therapeutic delivery. Compared to conventional hydrogel particles that are mainly composed of vinylic monomers, we have introduced a simple methodology to prepare multi-functional cationic hydrogel particles by adopting the epoxy-amine chemistry in water exemplifying "click" characteristics. Herein, we investigate the effects of key reaction parameters, including time, temperature, reactant concentration and amine-epoxy stoichiometric ratio, on the preparation and properties of such hydrogel particles. Our results indicated that the aforementioned parameters could greatly impact the particle formation. The hydrodynamic diameter, surface charge, and morphology of the resultant particles were characterized by dynamic light scattering and scanning electron microscopy. Particle size was inversely correlated with the following reaction parameters: reaction time, temperature, and reactant concentration. This is likely due to the influence of the parameters on the formation of the intermediate thermosensitive prepolymers. Different reaction conditions yielded a wide range of particle surface charges, varying from +47 mV to +71 mV. Morphological analysis also revealed significant effects induced by the variation of reaction time and temperature. All particles exhibited a temperature-dependent swelling property.However, the extent of swelling and sensitivity varied depending on the reaction conditions. Finally, in vitro cytocompatibility studies based on murine RAW264.7 macrophages showed the particle acute cytotoxicity being dose and surface charge dependent. Cytocompatibility of the cationic hydrogel particles was improved by reducing the surface charges with variation of the synthesis conditions. † Electronic supplementary information (ESI) available: SEM images of products collected from reactions based on amino hydrogen to epoxy stoichiometric ratios of 0.5 and 1; thermal responsiveness of the monomer JT403; intensity correlation curves of various hGPs; transmission electron microscopy (TEM) images of hGPs prepared using different reaction times; hGP stability in serum-containing culture medium; and phase contrast image of the non-treated macrophage control culture. See