Tuning the Elasticity of Nanogels Improves Their Circulation Time by Evading Immune Cells.

Peptide receptor radionuclide therapy is used to treat solid tumors by locally delivering radiation. However, due to nephro- and hepato-toxicity, it is limited by its dosage. To amplify radiation damage to tumor cells, radiolabeled nanogels can be used. We show that by tuning the mechanical properties of nanogels significant enhancement in circulation half-life of the gel could be achieved. We demonstrate why and how small changes in the mechanical properties of the nanogels influence its cellular fate. Nanogels with a storage modulus of 37 kPa were minimally phagocytosed by monocytes and macrophages compared to nanogels with 93 kPa modulus. Using PET/CT a significant difference in the blood circulation time of the nanogels was shown. Computer simulations affirmed the results and predicted the mechanism of cellular uptake of the nanogels. Altogether, this work emphasizes the important role of elasticity even for particles that are inherently soft such as nano- or microgels.

In-Line Characterization of the Temperature-Responsive Behavior of Surface-Bound Microgel Coatings by QCM-D: A Novel Strategy for Protein Repellence Evaluation.

In this work, quartz crystal microbalance with dissipation monitoring (QCM-D) was used to develop a new method to evaluate the protein repellency of microgel coatings. Compared to traditional protocols for surface analysis, QCM has the advantage of a real-time quantitative approach with high sensitivity, allowing us to describe variations of the adsorbed mass with unprecedented accuracy. To enable the detectability of the film throughout the whole operational temperature interval, a poly(N-isopropylacrylamide-co-glycidyl methacrylate) p(NIPAm-co-GMA) microgel monolayer with defined thickness and rigidity was designed. Covalent adhesion of the film to the silica surface was achieved by epoxy-thiol click chemistry and tested for repeated temperature cycles, showing substantial reproducibility. Further functionalization of microgel surfaces by grafting polyzwitterionic chains remarkably improved the protein repellence leaving the strong surface adhesion unaltered. Before and after exposure to fluorescein-tagged bovine serum albumin (FITC-BSA), the coatings showed identical responsive behavior, proving the absence of protein deposition. In nonrepellent coatings, QCM monitoring instead displayed a characteristic shift in the volume phase transition (VPT), pointing out the effect of adsorbed proteins on the swelling behavior of pNIPAm. The combination of QCM-D and UV-visible (UV-vis) was used to evaluate the effect of increasing surface coverage, enabling to distinguish between the protein deposition occurring over the coated and the uncoated portion of the sensor.

Electrospun Chitosan Functionalized with C12, C14 or C16 Tails for Blood-Contacting Medical Devices.

Medical applications stimulate the need for materials with broad potential. Chitosan, the partially deacetylated derivative of chitin, offers many interesting characteristics, such as biocompatibility and chemical derivatization possibility. In the present study, porous scaffolds composed of electrospun interwoven nanometric fibers are produced using chitosan or chitosan functionalized with aliphatic chains of twelve, fourteen or sixteen methylene groups. The scaffolds were thoroughly characterized by SEM and XPS. The length of the aliphatic tail influenced the physico-chemical and dynamic mechanical properties of the functionalized chitosan. The electrospun membranes revealed no interaction of Gram+ or Gram- bacteria, resulting in neither antibacterial nor bactericidal, but constitutively sterile. The electrospun scaffolds demonstrated the absence of cytotoxicity, inflammation response, and eryptosis. These results open the door to their application for blood purification devices, hemodialysis membranes, and vascular grafts.

Dual-Temperature-Responsive Microgels from a Zwitterionic Functional Graft Copolymer with Superior Protein Repelling Property.

In this work, we developed a synthetic strategy to synthesize dual-temperature-responsive low surface fouling zwitterionic microgels. Statistical poly(N-vinylcaprolactam-co-glycidyl methacrylate) copolymers were synthesized by RAFT polymerization and post-modified by thiol-epoxy click reaction with thiol end-group-modified poly(sulfobetaine) macro-RAFT (PSB-SH) to obtain poly(N-vinylcaprolactam-co-glycidyl methacrylate)-graft-poly(sulfobetaine) (PVCL-co-PGMA-g-PSB) graft copolymers. Synthesized graft copolymers were cross-linked by diamine cross-linker in water-in-oil (w/o) inverse mini-emulsion to obtain zwitterionic microgels. Using this approach, we synthesized microgels with unique microstructure, high loading and uniform distribution of poly(sulfobetaine) chains, which exhibits tunable dual-volume phase transition temperatures. The microgels also showed excellent antifouling property reflected in strongly reduced protein absorption on a microgel-coated surface observed in real time by a Quartz Crystal Microbalance with Dissipation (QCM-D) monitoring experiment with continuous flow of protein solution. Therefore, this kind of zwitterionic microgel can be potentially used for temperature-triggered drug delivery and anti-bioadhesion coating material as well.

Stimuli-Responsive Zwitterionic Core-Shell Microgels for Antifouling Surface Coatings.

Fouling on filtration membranes is induced by the nonspecific interactions between the membrane surface and the foulants, and effectively hinders their efficient use in various applications. Here, we established a facile method for the coating of membrane surface with a dual stimuli-responsive antifouling microgel system enriched with a high polyzwitterion content. Different poly(sulfobetaine) (PSB) zwitterionic polymers with defined molecular weights and narrow dispersities were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization and integrated onto poly(N-vinylcaprolactam) (PVCL) microgels via a controlled dosage of a cross-linker, adapting a precipitation polymerization technique to obtain a core-shell microstructure. Increasing the PSB macro-RAFT concentration resulted in a shift of both upper critical solution temperature and lower critical solution temperature toward higher temperatures. Cryogenic transmission electron microscopy at different temperatures suggested the formation of a core-shell morphology with a PVCL-rich core and a PSB-rich shell. On the other hand, the significant variations of different characteristic proton signals and reversible phase transitions of the microgel constituents were confirmed by temperature-dependent 1H NMR studies. Utilizing a quartz crystal microbalance with dissipation monitoring, we have been able to observe and quantitatively describe the antipolyelectrolyte behavior of the zwitterionic microgels. The oscillation frequency of the sensor proved to change reversibly according to the variations of the NaCl concentration, showing, in fact, the effect of the interaction between the salt and the opposite charges present in the microgel deposited on the sensor. Poly(ethersulfone) membranes, chosen as the model surface, when functionalized with zwitterionic microgel coatings, displayed protein-repelling property, stimulated by different transition temperatures, and showed even better performances at increasing NaCl concentration. These kinds of stimuli-responsive zwitterionic microgel can act as temperature-triggered drug delivery systems and as potential coating materials to prevent bioadhesion and biofouling as well.

Chitosan functionalization of titanium and Ti6Al4V alloy with chloroacetic acid as linker agent.

In this work, a new covalent grafting of chitosan on titanium and Ti6Al4V alloy surfaces is reported using chloroacetic acid as linker agent. Good results were obtained both on titanium and on Ti6Al4V alloy. The effect of the surface acid pretreatments on the subsequent functionalization with chitosan is evaluated. The morphological aspect of acid etched metal surfaces before chitosan grafting has been characterized by scanning electron microscopy (SEM). The presence of carboxylic groups on metal surfaces and then the efficiency of chitosan covalent immobilization were detected by Fourier transformed infrared-Attenuated Total Reflectance (FTIR-ATR) and X-Ray photoelectron spectroscopy (XPS). Cyclic voltammetry tests, using the functionalized titanium and Ti6Al4V samples as electrodes, were conducted in different aqueous solutions, to detect the presence of the homogeneous overlayer of chitosan on the surface, and to evaluate the importance of the carboxyl groups as linker agent.

Biocompatible Materials Based on Self-Assembling Peptides on Ti25Nb10Zr Alloy: Molecular Structure and Organization Investigated by Synchrotron Radiation Induced Techniques.

In this work, we applied advanced Synchrotron Radiation (SR) induced techniques to the study of the chemisorption of the Self Assembling Peptide EAbuK16, i.e., H-Abu-Glu-Abu-Glu-Abu-Lys-Abu-Lys-Abu-Glu-Abu-Glu-Abu-Lys-Abu-Lys-NH2 that is able to spontaneously aggregate in anti-parallel ß-sheet conformation, onto annealed Ti25Nb10Zr alloy surfaces. This synthetic amphiphilic oligopeptide is a good candidate to mimic extracellular matrix for bone prosthesis, since its ß-sheets stack onto each other in a multilayer oriented nanostructure with internal pores of 5-200 nm size. To prepare the biomimetic material, Ti25Nb10Zr discs were treated with aqueous solutions of EAbuK16 at different pH values. Here we present the results achieved by performing SR-induced X-ray Photoelectron Spectroscopy (SR-XPS), angle-dependent Near Edge X-ray Absorption Fine Structure (NEXAFS) spectroscopy, FESEM and AFM imaging on Ti25Nb10Zr discs after incubation with self-assembling peptide solution at five different pH values, selected deliberately to investigate the best conditions for peptide immobilization.