Fast Access to Amphiphilic Multiblock Architectures by the Anionic Copolymerization of Aziridines and Ethylene Oxide.

An ideal system for stimuli-responsive and amphiphilic (block) polymers would be the copolymerization of aziridines with epoxides. However, to date, no copolymerization of these two highly strained three-membered heterocycles had been achieved. Herein, we report the combination of the living oxy- and azaanionic ring-opening polymerization of ethylene oxide (EO) and sulfonamide-activated aziridines. In a single step, well-defined amphiphilic block copolymers are obtained by a one-pot copolymerization. Real-time 1H NMR spectroscopy revealed the highest difference in reactivity ratios ever reported for an anionic copolymerization (with r1 = 265 and r2 = 0.004 for 2-methyl- N-tosylaziridine/EO and r1 = 151 and r2 = 0.013 for 2-methyl- N-mesylaziridine/EO), leading to the formation of block copolymers with monomodal and moderate molecular weight distributions ( Mw/ Mn mostly ≤1.3). The amphiphilic diblock copolymers were used to stabilize emulsions and to prepare polymeric nanoparticles by miniemulsion polymerization, representing a novel class of nonionic and responsive surfactants. In addition, this unique comonomer reactivity of activated-Az/EO allows fast access to multiblock copolymers, and we prepared the first amphiphilic penta- or tetrablock copolymers containing aziridines in only one or two steps, respectively. These examples render the combination of epoxide and aziridine copolymerizations via a powerful strategy for producing sophisticated macromolecular architectures and nanostructures.

Controlling the Polymer Microstructure in Anionic Polymerization by Compartmentalization.

An ideal random anionic copolymerization is forced to produce gradient structures by physical separation of two monomers in emulsion compartments. One monomer (M) is preferably soluble in the droplets, while the other one (D) prefers the continuous phase of a DMSO-in-cyclohexane emulsion. The living anionic copolymerization of two activated aziridines is thus confined to the DMSO compartments as polymerization occurs selectively in the droplets. Dilution of the continuous phase adjusts the local concentration of monomer D in the droplets and thus the gradient of the resulting copolymer. The copolymerizations in emulsion are monitored by real-time 1 H NMR kinetics, proving a change of the reactivity ratios of the two monomers upon dilution of the continuous phase from ideal random to adjustable gradients by simple dilution.

Sequence-Controlled Polymers via Simultaneous Living Anionic Copolymerization of Competing Monomers.

Natural macromolecules, i.e., sequence-controlled polymers, build the basis for life. In synthetic macromolecular chemistry, reliable tools for the formation of sequence-controlled macromolecules are rare. A robust and efficient chain-growth approach based on the simultaneous living anionic polymerization of sulfonamide-activated aziridines for sequence control of up to five competing monomers resulting in gradient copolymers is presented. The simultaneous azaanionic copolymerization is monitored by real-time (1) H NMR spectroscopy for each monomer at any time during the reaction. The monomer sequence can be adjusted by the monomer reactivity, depending on the electron-withdrawing effect by the sulfonamide (nosyl-, brosyl-, tosyl-, mesyl-, busyl) groups. This method offers unique opportunities for sequence control by competing copolymerization: a step forward to well-engineered synthetic polymers with defined microstructures.

Microwave-Assisted Desulfonylation of Polysulfonamides toward Polypropylenimine.

Linear polyethylenimine (L-PEI) has been the gold standard for gene delivery and is typically prepared by hydrolysis from poly(2-oxazoline)s. Recently, also the anionic polymerization of activated aziridines was reported as a potential pathway toward linear and well-defined polyamines. However, only sulfonamide-activated aziridines so far undergo the living anionic polymerization and their desulfonylation was only reported scarcely. This is mainly due to the relatively high stability of the sulfonamides and the drastic change in solubility during the desulfonylation. Herein, we investigated the desulfonylation of such poly(aziridine)s prepared from tosylated or mesylated propyleneimine to afford linear polypropylenimine (L-PPI) as an alternative to L-PEI. Different desulfonylation strategies for tosylated (Ts) and mesylated (Ms) PPI were studied. The reductive cleavage of the sulfonamide with sodium bis(2-methoxy ethoxy) aluminum hydride yielded 80% of deprotected amine groups. Quantitative conversion to L-PPI was obtained, when the tosylated PPI was hydrolyzed under acidic conditions with pTsOH under microwave (MW) irradiation. The same treatment removed 90% of the mesyl groups from the mesylated PPI analog. The MW-assisted acidic hydrolysis represents a fast, inexpensive and easy approach in comparison to other methods, where complex reaction conditions and tedious purifications are major drawbacks, however some chain scission may occur. The high purity of the obtained products, in combination with the versatility of the activated aziridine chemistry, demonstrate many advantages of our strategy, especially for future biomedical implementations.

Assessing motivation to change in bulimia nervosa: the Bulimia Nervosa Stages of Change Questionnaire.

OBJECTIVE: To assess motivation to change in adolescent patients with bulimia nervosa through the Bulimia Nervosa Stages of Change Questionnaire (BNSOCQ), an instrument adapted from the Anorexia Nervosa Stages of Change Questionnaire (ANSOCQ) already validated in anorexic patients. METHOD: Subjects were 30 bulimia nervosa patients (mean age = 16.3 years) who were receiving treatment at an eating disorders unit. The evaluation instruments were: the BNSOCQ, the Eating Disorders Inventory (EDI-2) and the Beck Depression Inventory (BDI). The BNSOCQ was re-administered 1 week later to evaluate test-retest reliability. RESULTS: The BNSOCQ demonstrated good internal consistency (Cronbach's alpha = 0.94) and one week test-retest reliability (Pearson's r = 0.93). Negative significant correlations were found between the BNSOCQ and several EDI-2 scales (Pearson's r between -0.51 and -0.84) and the BDI (r = -0.74). CONCLUSION: The study provides initial support for the reliability and validity of the BNSOCQ as a self-report instrument for assessing motivation to change in adolescents with bulimia nervosa.

Multihydroxy Polyamines by Living Anionic Polymerization of Aziridines.

Acetal-protected and sulfonamide-activated aziridines (Az) have been prepared and polymerized by living anionic polymerization with molecular weight dispersities in most cases below D < 1.2 and controlled molecular weights. Three new monomers have been prepared varying in the length of the pendant chain. The resulting double protected polymers can be selectively deprotected in order to release the polyamine or the polyol structures. Detailed structural characterization was performed for all polymers, and chain extension proves their living polymerization behavior and the formation of block copolymers. Thermal analysis can be used in order to follow the deprotection steps. These new protected monomers broaden the scope of the azaanionic polymerization of aziridines and may find useful applications as well-defined functional poly(ethylene imine) derivatives.

The organocatalytic ring-opening polymerization of N-tosyl aziridines by an N-heterocyclic carbene.

The ring-opening polymerization of N-tosyl aziridines, in the presence of 1,3-bis(isopropyl)-4,5(dimethyl)imidazol-2-ylidene as an organocatalyst and an N-tosyl secondary amine as initiator mimicking the growing chain, provides the first metal-free route to well defined poly(aziridine)s (PAz) and related PAz-based block copolymers.

Controlled implant/soft tissue interaction by nanoscale surface modifications of 3D porous titanium implants.

Porous titanium implants are widely employed in the orthopaedics field to ensure good bone fixation. Recently, the use of porous titanium implants has also been investigated in artificial larynx development in a clinical setting. Such uses necessitate a better understanding of the interaction of soft tissues with porous titanium structures. Moreover, surface treatments of titanium have been generally evaluated in planar structures, while the porous titanium implants have complex 3 dimensional (3D) architectures. In this study, the determining factors for soft tissue integration of 3D porous titanium implants were investigated as a function of surface treatments via quantification of the interaction of serum proteins and cells with single titanium microbeads (300-500 µm in diameter). Samples were either acid etched or nanostructured by anodization. When the samples are used in 3D configuration (porous titanium discs of 2 mm thickness) in vivo (in subcutis of rats for 2 weeks), a better integration was observed for both anodized and acid etched samples compared to the non-treated implants. If the implants were also pre-treated with rat serum before implantation, the integration was further facilitated. In order to understand the underlying reasons for this effect, human fibroblast cell culture tests under several conditions (directly on beads, beads in suspension, beads encapsulated in gelatin hydrogels) were conducted to mimic the different interactions of cells with Ti implants in vivo. Physical characterization showed that surface treatments increased hydrophilicity, protein adsorption and roughness. Surface treatments also resulted in improved adsorption of serum albumin which in turn facilitated the adsorption of other proteins such as apolipoprotein as quantified by protein sequencing. The cellular response to the beads showed considerable difference with respect to the cell culture configuration. When the titanium microbeads were entrapped in cell-laden gelatin hydrogels, significantly more cells migrated towards the acid etched beads. In conclusion, the nanoscale surface treatment of 3D porous titanium structures can modulate in vivo integration by the accumulative effect of the surface treatment on several physical factors such as protein adsorption, surface hydrophilicity and surface roughness. The improved protein adsorption capacity of the treated implants can be further exploited by a pre-treatment with autologous serum to render the implant surface more bioactive. Titanium microbeads are a good model system to observe these effects in a 3D microenvironment and provide a better representation of cellular responses in 3D.

Multi-scale modification of metallic implants with pore gradients, polyelectrolytes and their indirect monitoring in vivo.

Metallic implants, especially titanium implants, are widely used in clinical applications. Tissue in-growth and integration to these implants in the tissues are important parameters for successful clinical outcomes. In order to improve tissue integration, porous metallic implants have being developed. Open porosity of metallic foams is very advantageous, since the pore areas can be functionalized without compromising the mechanical properties of the whole structure. Here we describe such modifications using porous titanium implants based on titanium microbeads. By using inherent physical properties such as hydrophobicity of titanium, it is possible to obtain hydrophobic pore gradients within microbead based metallic implants and at the same time to have a basement membrane mimic based on hydrophilic, natural polymers. 3D pore gradients are formed by synthetic polymers such as Poly-L-lactic acid (PLLA) by freeze-extraction method. 2D nanofibrillar surfaces are formed by using collagen/alginate followed by a crosslinking step with a natural crosslinker (genipin). This nanofibrillar film was built up by layer by layer (LbL) deposition method of the two oppositely charged molecules, collagen and alginate. Finally, an implant where different areas can accommodate different cell types, as this is necessary for many multicellular tissues, can be obtained. By, this way cellular movement in different directions by different cell types can be controlled. Such a system is described for the specific case of trachea regeneration, but it can be modified for other target organs. Analysis of cell migration and the possible methods for creating different pore gradients are elaborated. The next step in the analysis of such implants is their characterization after implantation. However, histological analysis of metallic implants is a long and cumbersome process, thus for monitoring host reaction to metallic implants in vivo an alternative method based on monitoring CGA and different blood proteins is also described. These methods can be used for developing in vitro custom-made migration and colonization tests and also be used for analysis of functionalized metallic implants in vivo without histology.