Synthesis of Polyampholyte Janus-like Microgels by Coacervation of Reactive Precursors in Precipitation Polymerization.

Controlling the distribution of ionizable groups of opposite charge in microgels is an extremely challenging task, which could open new pathways to design a new generation of stimuli-responsive colloids. Herein, we report a straightforward approach for the synthesis of polyampholyte Janus-like microgels, where ionizable groups of opposite charge are located on different sides of the colloidal network. This synthesis approach is based on the controlled self-assembly of growing polyelectrolyte microgel precursors during the precipitation polymerization process. We confirmed the morphology of polyampholyte Janus-like microgels and demonstrate that they are capable of responding quickly to changes in both pH and temperature in aqueous solutions.

Electrostatically Driven Guest Binding in Self-Assembled Molecular Network of Hexagonal Pyridine Macrocycle at the Liquid/Solid Interface: Symmetry Breaking Induced by Coadsorbed Solvent Molecules.

We present here the construction of a self-assembled two-dimensional network at the liquid/solid interface using a hexagonal pyridine macrocycle which binds an organic cation in its intrinsic porous space by electrostatic interactions. For this purpose, a hexagonal pyridinylene-butadiynylene macrocycle (PyBM) having six octyloxymethyl groups, PyBM-C8, was synthesized. As guests, tropylium (Tr) tetrafluoroborate and trioxatriangulenium (TOTA) hexafluorophosphate were used. In this study, we focused on (i) the network patterns of PyBM-C8 which change in response to its concentration and (ii) the position of the guest immobilized in the porous space of the macrocycle. Scanning tunneling microscopy (STM) observations at the interface of 1,2,4-trichlorobenzene (TCB) and highly oriented pyrolytic graphite (HOPG) revealed that PyBM-C8 formed four different polymorphs, oblique, loose hexagonal, linear, and rectangular, depending on the solute concentration and annealing treatment. Solvent TCB molecules are likely coadsorbed to not only the intrinsically porous space of PyBM-C8 (internal TCB) but also the space outside of the macrocycle between its alkyl chains (external TCB) in most of the cases. Upon adding the guest cation, whereas small Tr was not visualized in the pore due to size mismatching, larger TOTA was clearly observed in each pore. In addition, based on high-resolution STM images of the rhombus packing pattern of PyBM-C8, we revealed experimentally that TOTA was placed at an off-center position of the deformed hexagonal macrocyclic core in the rhombus pattern. On the basis of the molecular mechanics calculations, we hypothesize that the off-center location of TOTA is due to deformation of the hexagonal macrocycle through interaction with two external TCB molecules located at opposite edges of the macrocyclic core. Symmetry breaking of the macrocyclic host framework induced by coadsorbed surrounding solvent molecules thus plays a significant role in host-guest complexation at the liquid/solid interface.

Functional Isoeugenol-Modified Nanogel Coatings for the Design of Biointerfaces.

A new route for the synthesis of functional aqueous nanogels decorated with a controlled amount of surface-drafted isoeugenol molecules has been developed. Obtained nanogels exhibit two key functions: a) antibacterial activity against different oral pathogens and b) cell-adhesive and -growth-promoting properties. Functional nanogels can be potentially used as building blocks in the design of bioactive coatings on various implants preventing infections and accelerating tissue regeneration.

Trypsin-Free Cultivation of 3D Mini-Tissues in an Adaptive Membrane Bioreactor.

The production of large scaffold-free tissues is a key challenge in regenerative medicine. Nowadays, temperature-responsive polymers allow intact tissue harvesting without needing proteolytic enzymes. This method is limited to tissue culture plastic with limited upscaling capacity and plain process control. Here, a thermoresponsive hollow fiber membrane bioreactor is presented to produce large scaffold-free tissues. Intact tissues, rich in cell-to-cell connections and ECM, are harvested from a poly(N-vinylcaprolactam) microgel functionalized poly(ether sulfone)/poly(vinylpyrrolidone) hollow fiber membrane by a temperature shift. The harvested 3D tissues adhere in successive cultivation and exhibit high vitality for several days. The facile adsorptive coating waives the need for extensive surface treatment. The research is anticipated to be a starting point for upscaling the production of interconnected tissues enabling new opportunities in regenerative medicine, large-scale drug screening on physiological relevant tissues, and potentially opening new chances in cell-based therapies.

Synthesis of Poly(N-vinylcaprolactam)-Based Microgels by Precipitation Polymerization: Pseudo-Bulk Model for Particle Growth and Size Distribution.

Particle size distribution and in particular the mean particle size are key properties of microgels, which are determined by synthesis conditions. To describe particle growth and particle size distribution over the progress of synthesis of poly(N-vinylcaprolactam)-based microgels, a pseudo-bulk model for precipitation copolymerization with cross-linking is formulated. The model is fitted and compared to experimental data from reaction calorimetry and dynamic light scattering, showing good agreement with polymerization progress, final particle size, and narrow particle size distribution. Predictions of particle growth and reaction progress for different experimental setups are compared to the corresponding experimental data, demonstrating the predictive capability and limitations of the model. The comparison to reaction calorimetry measurements shows the strength in the prediction of the overall polymerization progress. The results for the prediction of the particle radii reveal significant deviations and highlight the demand for further investigation, including additional data.

Direct Monitoring of Microgel Formation during Precipitation Polymerization of N-Isopropylacrylamide Using in Situ SANS.

Poly(N-isopropylacrylamide) microgels have found various uses in fundamental polymer and colloid science as well as in different applications. They are conveniently prepared by precipitation polymerization. In this reaction, radical polymerization and colloidal stabilization interact with each other to produce well-defined thermosensitive particles of narrow size distribution. However, the underlying mechanism of precipitation polymerization has not been fully understood. In particular, the crucial early stages of microgel formation have been poorly investigated so far. In this contribution, we have used small-angle neutron scattering in conjunction with a stopped-flow device to monitor the particle growth during precipitation polymerization in situ. The average particle volume growth is found to follow pseudo-first order kinetics, indicating that the polymerization rate is determined by the availability of the unreacted monomer, as the initiator concentration does not change considerably during the reaction. This is confirmed by calorimetric investigation of the polymerization process. Peroxide initiator-induced self-crosslinking of N-isopropylacrylamide and the use of the bifunctional crosslinker N,N'-methylenebisacrylamide are shown to decrease the particle number density in the batch. The results of the in situ small-angle neutron scattering measurements indicate that the particles form at an early stage in the reaction and their number density remains approximately the same thereafter. The overall reaction rate is found to be sensitive to monomer and initiator concentration in accordance with a radical solution polymerization mechanism, supporting the results from our earlier studies.

From Batch to Continuous Precipitation Polymerization of Thermoresponsive Microgels.

Microgels are commonly synthesized in batch experiments, yielding quantities sufficient to perform characterization experiments for physical property studies. With increasing attention on the application potential of microgels, little attention is yet paid to the questions (a) whether they can be produced continuously on a larger scale, (b) whether synthesis routes can be easily transferred from batch to continuous synthesis, and (c) whether their properties can be precisely controlled as a function of synthesis parameters under continuous flow reaction conditions. We present a new continuous synthesis process of two typical but different microgel systems. Their size, size distribution, and temperature-responsive behavior are compared in depth to those of microgels synthesized using batch processes, and the influence of premixing and surfactant is also investigated. For the surfactant-free poly( N-vinylcaprolactam) and poly( N-isopropylacrylamide) systems, microgels are systematically smaller, while the actual size is depending on the premixing of the reaction solutions. However, by the use of a surfactant, the size difference between batch and continuous preparation diminishes, resulting in equal-sized microgels. Temperature-induced swelling-deswelling of microgels synthesized under continuous flow conditions was similar to that of their analogues synthesized using the batch polymerization process. Additionally, investigation of the internal microgel structure using static light scattering showed no significant changes between microgels prepared under batch and continuous conditions. The work encourages synthesis concepts of sequential chemical conditions in continuous flow reactors to prepare precisely tuned new microgel systems.

In-line Monitoring of Monomer and Polymer Content During Microgel Synthesis Using Precipitation Polymerization via Raman Spectroscopy and Indirect Hard Modeling.

This contribution presents in-line monitoring of microgel synthesis by precipitation polymerization based on Raman spectroscopy. The spectra are evaluated via multivariate Indirect Hard Modeling (IHM) regression. Therefore, mechanistic models of the pure component spectra for solvent, monomer, and microgel are created by a sum of adaptable parameterized peak functions (Gaussian-Lorentzian). Instead of individual calibrations for each analyte, one comprehensive model is calibrated to predict both the monomer and microgel fraction while ensuring a consistent mass balance. As a novelty, this leads to an in-line microgel quantification based on an interactive spectral model. The results show cross-validation errors (RMSECV) of monomer and microgel fractions as low as 0.028 wt % and 0.084 wt %, respectively. The ability of IHM to account for non-linear spectral changes was found to reduce the microgel RMSECV by a factor of two compared to linear CLS regression. The calibration model allows simultaneous observation of the decrease in monomer content and the formation of microgels. Long as well as short focus immersion optics reveal characteristic vibrations of the turbid microgel suspension, although long focus optics are influenced by scattering particles to a greater extent. Precise examination of the model proves that the prediction is robust against changes in microgel particle size or temperature, which opens up the application of Raman spectroscopy as a comprehensive process analytical technology in microgel synthesis.

Stimuli-responsive poly(N-vinylcaprolactam-co-2-methoxyethyl acrylate) core-shell microgels: facile synthesis, modulation of surface properties and controlled internalisation into cells.

Herein we report the synthesis of biocompatible stimuli-responsive core-shell microgels consisting of a poly(N-vinylcaprolactam) (PVCL) core and a poly(2-methoxyethyl acrylate) (PMEA) corona via one-step surfactant-free precipitation copolymerization. The copolymerization process was investigated by reaction calorimetry, microgel growth was monitored by in situ dynamic light scattering and the chemical structure of core-shell microgels was characterized by Raman spectroscopy. It was possible to incorporate up to 32 mol% MEA into the PVCL/MEA microgels without loss of colloidal stability and broadening of the size distribution. The core-shell morphology of microgels was confirmed by transverse magnetization relaxation 1H-NMR, dynamic light scattering (DLS), atomic force microscopy (AFM) and viscosimetry. By means of the NMR data, calorimetry and viscosity measurements it could be shown that MEA is mainly located in the microgel shell. This leads to hindered temperature-induced swelling and collapsing of the PVCL-core, as demonstrated by DLS measurements, due to the fact that the PMEA-shell exhibits a very low LCST around 5 °C. These results could also be confirmed by AFM: an increasing MEA-content leads to the formation of dense and compact core-shell microgels and results in a loss of their softness and deformability. Due to the presence of the PMEA-shell these microgels can be endocytosed much faster by HeLa cells maintaining their viability and can be suitable candidates for the design of drug carriers or imaging/diagnostic systems.