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Currently, most of the clinically available surgical glues and sealants lack elasticity, good adhesion and biocompatibility properties. Hydrogels as tissue adhesives have received extensive attention for their tissue-mimicking features. Here, a novel surgical glue hydrogel based on a fermentation-derived human albumin (rAlb) and biocompatible crosslinker for tissue-sealant applications has been developed. In order to reduce the risks of viral transmission diseases and an immune response, Animal-Free Recombinant Human Albumin from the saccharomyces yeast strain was used. A more biocompatible crosslinking agent, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), was used and compared with glutaraldehyde (GA). The design of crosslinked albumin-based adhesive gels was optimized by varying the albumin concentration, the mass ratio between albumin and the crosslinking agent as well as the crosslinker type. Tissue sealants were characterized in terms of mechanical (tensile and shear), adhesive and in vitro biocompatibility properties. The results indicated that the mechanical and adhesive properties improved as the albumin concentration increased and the mass ratio between albumin and crosslinker decreased. Moreover, the EDC-crosslinked albumin gels have better biocompatibility properties than GA-crosslinked glues.

This study investigates the effects of different molecular weight hyaluronic acids (HAs) on the mucosal nanostructure using a pig stomach mucin hydrogel as a mucosal barrier model. Microparticles (1.0 μm) and nanoparticles (200 nm) were used as probes, and their movement in mucin was studied by a three-dimensional confocal microscopy-based particle tracking technique and by Nanoparticle Tracking Analysis (NTA) after addition of high-molecular weight (900 kDa) and low-molecular weight (33 kDa) HA. This demonstrated a molecular weight-dependent HA modulation of the mucin nanostructure with a 2.5-fold decrease in the mobility of 200 nm nanoparticles. To further investigate these mechanisms and to verify that the natural viscoelastic properties of mucus are not undesirably altered, rheological measurements were performed on mucin hydrogels with or without HA. This suggested the observed particle mobility restriction was not attributed to alterations of the natural mucin cohesive and viscoelastic properties but, instead, indicates that the added high-molecular weight HA primarily modulates the mucin nanostructure and mesh size. This study, hereby, demonstrates how mucus nanostructure can be modulated by the addition of high-molecular weight HA that offers an opportunity to control mucosal pathogenesis and drug delivery.

Major challenges for the clinical translation of small interfering RNA (siRNA) include overcoming the poor plasma half-life, site-specific delivery and modulation of gene silencing. In this work, we exploit the intrinsic transport properties of human serum albumin to tune the blood circulatory half-life, hepatic accumulation and gene silencing; based on the number of siRNA cholesteryl modifications. We demonstrate by a gel shift assay a strong and specific affinity of recombinant human serum albumin (rHSA) towards cholesteryl-modified siRNA (Kd>1×10(-7)M) dependent on number of modifications. The rHSA/siRNA complex exhibited reduced nuclease degradation and reduced induction of TNF-α production by human peripheral blood mononuclear cells. The increased solubility of heavily cholesteryl modified siRNA in the presence of rHSA facilitated duplex annealing and consequent interaction that allowed in vivo studies using multiple cholesteryl modifications. A structural-activity-based screen of in vitro EGFP-silencing was used to select optimal siRNA designs containing cholesteryl modifications within the sense strand that were used for in vivo studies. We demonstrate plasma half-life extension in NMRI mice from t1/2 12min (naked) to t1/2 45min (single cholesteryl) and t1/2 71min (double cholesteryl) using fluorescent live bioimaging. The biodistribution showed increased accumulation in the liver for the double cholesteryl modified siRNA that correlated with an increase in hepatic Factor VII gene silencing of 28% (rHSA/siRNA) compared to 4% (naked siRNA) 6days post-injection. This work presents a novel albumin-mediated cholesteryl design-based strategy for tuning pharmacokinetics and systemic gene silencing., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purpose: In this work we specifically investigate the molecular weight (Mw) dependent combinatorial properties of hyaluronic acid (HA) for exhibiting stealth and targeting properties using different Mw HA nanoshells to tune nanoparticle retargeting to CD44-expressing cancer cells., Methods: HA of different Mw was covalently grafted onto model polystyrene nanoparticles and advanced surface analysis by X-ray photoelectron spectroscopy performed to quantify and evaluate the effect of the coating procedure. Specific CD44-mediated retargeting was investigated by flow cytometry and confocal microscopy using isogenic D44-deficient and CD44-expressing MCF-7 breast adenocarcinoma cells., Results: Surface analysis demonstrated effective surface coating with 33, 260 and 900 kDa HA resulting in increased colloidal stability and highly negative surface charge due to presentation of up to 4.7% carboxyl groups that indicates an extended and non-constricted HA polymer surface. Reduced non-specific particle interaction in CD44(-) cells was shown for all HA nanoshells but CD44-dependent cellular retargeting and internalization in CD44(+) cells was highly dependent on the coating HA Mw properties., Conclusion: The combination of advanced surface characterization and evaluation of particle interactions in isogenic cells with and without CD44 receptor demonstrates direct evidence for the dual capacity of HA for stealth and CD44-mediated retargeting tunable by the HA molecular weight.

Hyaluronic acid (HA) hydrogels, obtained by cross-linking HA molecules with divinyl sulfone (DVS) based on a simple, reproducible, and safe process that does not employ any organic solvents, were developed. Owing to an innovative preparation method the resulting homogeneous hydrogels do not contain any detectable residual cross-linking agent and are easier to inject through a fine needle. HA hydrogels were characterized in terms of degradation and biological properties, viscoelasticity, injectability, and network structural parameters. They exhibit a rheological behaviour typical of strong gels and show improved viscoelastic properties by increasing HA concentration and decreasing HA/DVS weight ratio. Furthermore, it was demonstrated that processes such as sterilization and extrusion through clinical needles do not imply significant alteration of viscoelastic properties. Both SANS and rheological tests indicated that the cross-links appear to compact the network, resulting in a reduction of the mesh size by increasing the cross-linker amount. In vitro degradation tests of the HA hydrogels demonstrated that these new hydrogels show a good stability against enzymatic degradation, which increases by increasing HA concentration and decreasing HA/DVS weight ratio. Finally, the hydrogels show a good biocompatibility confirmed by in vitro tests.

The idea of this study was to combine hyaluronic acid (HA) viscosupplementation and a local/controlled delivery of a hydrophobic anti-inflammatory drug. To this aim, we investigated the ability of an octenyl succinic anhydride (OSA) modified HA (OSA-HA), to act as a solubility enhancer and as a platform for slow release of hydrophobic drug(s). This novel HA derivative could act as a viscosupplementation agent and, for this reason, a rheological study was conducted along with calorimetric analysis. Differential scanning calorimetry (DSC) results revealed that the ability of HA to sequester water is enhanced by the introduction of lipophilic functions within HA molecules, resulting in a decrease of the fraction of free water able to freeze compared to the unmodified HA. Moreover, OSA-HA solutions appear to be an appropriate tool to be used in viscosupplementation therapy owing to their suitable viscoelastic features. Our results indicate that OSA-HA is able to self-assemble into micelles, load a hydrophobic drug and release the active molecule with controlled kinetics. In particular, the analysis of release profiles showed that, in all cases, drug diffusion into the gel is faster compared to gel/drug dissolution, being the dissolution contribution more relevant as the OSA-HA concentration increases., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

1-Deoxymannojirimycin (8c) was synthesised from 2-amino-6-bromo-2,6-dideoxy-D-mannono-1,4-lactone (7) by intramolecular direct displacement of the C-6 bromine employing non-aqueous base treatment followed by reduction of the intermediate methyl ester. Likewise, using aqueous base at pH 12, ring closure took place by 5-exo attack on the 5,6-epoxide leading to 2,5-dideoxy-2,5-imino-L-gulonic acid (9b), which was reduced to 2,5-dideoxy-2,5-imino-D-glucitol (9b). The method was further applied to 2-amino-6-bromo-2,6-dideoxy-D-galacto- as well as D-talo-1,4-lactones (14 and 15). However, only the corresponding six-membered ring 1,5-iminuronic acid mimetics, namely (2R,3R,4S,5R)-3,4,5-trihydroxypipecolic acid (2,6-dideoxy-2,6-imino-D-galactonic acid, 16) and (2S,3R,4S,5R)-3,4,5-trihydroxypipecolic acid (2,6-dideoxy-2,6-imino-D-talonic acid, 17), were obtained. The corresponding enantiomers, L-galacto- as well as L-talo-2-amino-6-bromo-2,6-dideoxy-1,4-lactones ent-14 and ent-15, reacted accordingly to give the D-galacto- and L-altro-1,5-iminuronic acid mimetics, (2S,3S,4R,5S)-3,4,5-trihydroxypipecolic acid (2,6-dideoxy-2,6-imino-L-galactonic acid, ent-16) and (2R,3S,4R,5S)-3,4,5-trihydroxypipecolic acids (2,6-dideoxy-2,6-imino-L-talonic acid, ent-17), respectively.