Polyamides based on a partially bio-based spirodiamine

In this study novel, fully and partially bio-based polyamides containing spiroacetal moieties in the backbone derived from bio-glycerol and bio-ethanol were prepared and characterized. The renewable diamine employed to obtain a series of polyamides was synthesized by means of thiolene click chemistry and therefore contains flexible thioether as well as rigid spiroacetal moieties. Two different chemical pathways for the polymerization were investigated and evaluated. The polymerization of polyamide salts proved to be the most promising method and therefore salt polymerization was applied in the synthesis of polyamides with aliphatic and aromatic di-carboxylic acids. Subsequently, the structure of the polymers was confirmed by Maldi-ToF analysis and additionally thermal and mechanical properties were investigated revealing T-g's between 24 and 80 degrees C and ductile materials with moduli between 1.0 and 1.5 GPa. Both semicrystalline and amorphous polyamides were thermally stable and therefore suitable for thermal processing. In the end, degradation studies were performed on the acetal containing polyamides which showed that the polymers were stable at pH 3 and higher

Cardiopoietic cell therapy for advanced ischemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial

Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort

Requirements for immune recognition and processing of factor VIII by antigen-presenting cells

Generation of inhibitory antibodies upon repeated FVIII infusion represents a major complication in hemophilia care. Professional antigen presenting cells (APCs) are crucial for orchestration of humoral immune responses. APCs are capable of internalizing soluble as well as particulate antigens through various mechanisms resulting in loading of antigen-derived peptides on MHC class I or II for presentation to T cells. This review highlights how FVIII is recognized and processed by APCs. The significance and contribution of candidate receptors involved in FVIII uptake by APC are discussed. Recent findings defining the repertoire of FVIII peptides presented on MHC class II are addressed. Studies in murine models of hemophilia A suggest that modulation of APC function can reduce inhibitor formation. Based on this we anticipate that modulation of FVIII uptake by APCs may yield novel therapeutic approaches for treatment or prevention of inhibitor formation in patients with hemophilia A. (C) 2011 Elsevier Ltd. All rights reserve

Limited promiscuity of HLA-DRB1 presented peptides derived of blood coagulation factor VIII.

The formation of inhibitory antibodies directed against coagulation factor VIII (FVIII) is a severe complication in the treatment of hemophilia A patients. The induction of anti-FVIII antibodies is a CD4(+) T cell-dependent process. Activation of FVIII-specific CD4(+) T cells is dependent on the presentation of FVIII-derived peptides on MHC class II by antigen-presenting cells. Previously, we have shown that FVIII-pulsed human monocyte-derived dendritic cells can present peptides from several FVIII domains. In this study we show that FVIII peptides are presented on immature as well as mature dendritic cells. In immature dendritic cells half of the FVIII-loaded MHC class II molecules are retained within the cell, whereas in LPS-matured dendritic cells the majority of MHC class II/peptide complexes is present on the plasma membrane. Time-course studies revealed that presentation of FVIII-derived peptides was optimal between 12 and 24 hours after maturation but persisted for at least 96 hours. We also show that macrophages are able to internalize FVIII as efficiently as dendritic cells, however FVIII was presented on MHC class II with a lower efficiency and with different epitopes compared to dendritic cells. In total, 48 FVIII core-peptides were identified using a DCs derived of 8 different donors. Five HLA-promiscuous FVIII peptide regions were found - these were presented by at least 4 out of 8 donors. The remaining 42 peptide core regions in FVIII were presented by DCs derived from a single (30 peptides) or two to three donors (12 peptides). Overall, our findings show that a broad repertoire of FVIII peptides can be presented on HLA-DR

Solvent-Free Method for the Copolymerization of Labile Sugar-Derived Building Blocks into Polyamides

This research focuses on the preparation of biobased copolyamides containing biacetalized galactaric acid (GalX), namely, 2,3:4,5-di-<i>O</i>-isopropylidene-galactaric acid (GalXMe) and 2,3:4,5-di-<i>O</i>-methylene-galactaric acid (GalXH), in bulk by melt polycondensation of salt monomers. In order to allow the incorporation of temperature-sensitive sugar-derived building blocks into copolyamides at temperatures below the degradation temperature of the monomers and below their melting temperatures, a clever selection of salt monomers is required, such that the sugar-derived salt monomer dissolves in the other salt monomers. The polymerization was investigated by temperature dependent FT-IR and optical microscopy. The structure of the obtained copolyamides was elucidated by NMR and matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) techniques. The positive outcome of this modified polycondensation method depends on the solubility of sugar-derived polyamide salts in polyamide salts of comonomers and the difference between their melting temperatures, however does not depend on the melting temperature of the used sugar-derived monomer. A variety of comonomers was screened in order to establish the underlying mechanisms of the process

Towards sugar-derived polyamides as environmentally friendly materials

As part of our ongoing study investigating isohexide-based polyamides, we have synthesized isosorbide(bis(propan-1-amine)) (DAPIS) and studied its reactivity in the polymerization towards fully biobased polyamides. Polycondensation of nylon salts with various contributions of DAPIS afforded a family of homo- and copolyamides, which were characterized using complementary spectroscopic techniques. The chemical structure of the materials was determined by FT-IR, 1D and 2D liquid-state NMR spectroscopy, whilst the supramolecular arrangement, conformational changes upon heating, and molecular mobility of the polymers were investigated by solid-state 13C{1H} Cross-Polarization/Magic-Angle Spinning (CP/MAS) NMR and 13C{1H} Insensitive Nuclei Enhanced by Polarization Transfer (INEPT) experiments. The abundance of the different DAPIS conformers was determined by DFT-D computational methods. The thermal properties of the polyamides were tested for polymers with different amounts of isohexide units in the backbone by DSC and TGA, demonstrating that the increasing amounts of isohexide diamines efficiently decrease their melting points and slightly decrease their thermal stability. The relaxation processes of the isohexide-derived polyamides were studied by DMTA

Modification of an exposed loop in the C1 domain reduces immune responses to factor VIII in hemophilia A mice

Development of neutralizing Abs to blood coagulation factor VIII (FVIII) provides a major complication in hemophilia care. In this study we explored whether modulation of the uptake of FVIII by APCs can reduce its intrinsic immunogenicity. Endocytosis of FVIII by professional APCs is significantly blocked by mAb KM33, directed toward the C1 domain of FVIII. We created a C1 domain variant (FVIII-R2090A/K2092A/F2093A), which showed only minimal binding to KM33 and re-tained its activity as measured by chromogenic assay. FVIII-R2090A/K2092A/F2093A displayed a strongly reduced internalization by human monocyte-derived dendritic cells and macrophages, as well as murine BM-derived dendritic cells. We subsequently investigated the ability of this variant to induce an immune response in FVIII-deficient mice. We show that mice treated with FVIII-R2090A/ K2092A/F2093A have significantly lower anti-FVIII Ab titers and FVIII-specific CD4(+) T-cell responses compared with mice treated with wild-type FVIII. These data show that alanine substitutions at positions 2090, 2092, and 2093 reduce the immunogenicity of FVIII. According to our findings we hypothesize that FVIII variants displaying a reduced uptake by APCs provide a novel therapeutic approach to reduce inhibitor development in hemophilia A. (Blood. 2012;119(22):5294-5300

Hemicellulosic Sugars and Lignin:A Synergistic Combination for the Synthesis of High-Performance Bioresins

To render biorefineries economically viable, it isimportant to maximize the value of all of the processedlignocellulosic biomass. However, the hemicellulose fraction isoften overlooked in current biorefinery strategies. In this study, wedemonstrate the valorization of lignin and sugars, both obtainedthrough dilute acid solvolysis of lignocellulosic biomass, for theproduction of lignin/sugar-based polyurethane (LSPU) films aspartial substitutes for petroleum-derived polyols. LSPU films wereprepared using a four-component system, comprising lignin,hemicellulose-derived sugars, polytetrahydrofuran, and hexamethylene diisocyanate isocyanurate trimer. Our study involvedoptimizing the sugar content in the LSPU film formulations toinvestigate how the presence of sugar impacts the films’ structural,thermal, and mechanical properties. The results showed that as the concentration of sugar increased, the mechanical properties ofthe LSPU films were improved in comparison to those of sugar-free samples. Additionally, the LSPUs were evaluated as PUadhesives, where the mechanical properties of the bonded joints, comprising wood substrates, were measured using single-lap sheartests. The shear strength values obtained were comparable to or even higher than those of a commercial PU glue. Our findingsdemonstrate the potential of incorporating hemicellulose-derived sugars in LSPUs for improved mechanical and adhesion properties,offering new possibilities for the valorization of lignocellulosic derivatives

Rational design of small molecules targeting the C2 domain of coagulation factor VIII

The C domains of coagulation factors V (FV) and VIII (FVIII) are structurally conserved domains and share a common and essential function in membrane binding. In vivo regulation of thrombin formation strongly depends on the expression and regulation of the cofactor activities of FVIII and FV. With this study, we explored the possibility of inhibition of thrombin formation in full blood with small druglike molecules. Such compounds may serve as lead molecules for the development of a new type of orally available coagulation inhibitors that act by blocking the interaction between the C domains of FVIII and the membrane surface. We identified 9 novel molecules that are able to inhibit binding of the FVIII C2 domain to a model membrane by application of a combined ligand-based and target structure-based virtual screening approach that took into account the knowledge of a set of previously identified low-molecular-weight FVIII binders that were, however, not active in full blood. The half-maximal inhibitory concentration values of our newly identified compounds varied from 2.1 to 19.9 µM, of which 7 of 9 molecules did not appreciably inhibit FV membrane binding and were thus specific for FVIII. The most active bioactive compound showed activity in both plasma and in full bloo