Hyaluronic acid auto-crosslinked polymer (ACP): Reaction monitoring, process investigation and hyaluronidase stability

Hyaluronic Acid (HA) is a non-sulphated glycosaminoglycan that, despite its high molecular weight, is soluble in water and is not resistant to enzymatic degradation, the latter of which hinders its wider application as a biomedical material. Auto-crosslinked polymer (ACP) gels of HA are fully biocompatible hydrogels that exhibit improved viscoelastic properties and prolonged in vivo residence times compared to the native polymer. Crosslinking is achieved through a base-catalysed reaction consisting of the activation of HA carboxyl groups by 2-chloro-1-methylpyridinium iodide (CMPI) and subsequent nucleophilic acyl substitution by the hydroxyl groups of HA in organic solvent. In this study, a number of ACP hydrogels have been obtained via reactions using varying ratios of CMPI to HA. The crosslinking reaction was monitored by rheological measurements in organic solvents during CMPI addition to the reaction mixture. The ACP intermediates, powders and hydrogels were characterized, helping to elucidate the crosslinking process. A two-step mechanism was proposed to explain the observed trends in viscosity and particle size. Syntheses were carried out by varying the reaction temperature, respectively at 0 °C, 25 °C and 45 °C in N-Methyl-2-Pyrrolidone (NMP), as well as the solvent respectively in NMP, DMSO and DMF at 25 °C. Interestingly, varying these parameters did not substantially affect the degree of crosslinking but likely did influence the intra/inter-molecular crosslinking ratio and, therefore, the viscoelastic properties. A wide range of crosslinking densities was confirmed through ESEM analysis. Finally, a comparative hyaluronidase degradation assay revealed that the ACPs exhibited a higher resistance toward enzymatic cleavage at low elastic modulus compared to other more chemically resistant, crosslinked HAs. These observations demonstrated the importance of crosslinking density of matrix structures on substrate availability

Dopamine-functionalized sulphated hyaluronic acid as a titanium implant coating enhances biofilm prevention and promotes osseointegration

A series of new hyaluronan derivatives was synthesized and tested as an antibiotic release system by antibacterial and osseointegration assays. Specifically, partially sulphated hyaluronic acid (sHA) was functionalized with dopamine (DA). The DA moiety guarantees good performance as a binding agent for coating a titanium alloy surface; furthermore, the negatively charged sHA has bone regenerative effects and a high binding affinity for positively charged antibiotics. A sHA scaffold with a defined degree of sulphation (DS =2) was selected as a good compromise between a high negative charge density and poor heparin-like anticoagulant activity, while the degree of DA derivatization (17.1%mol) was chosen based on the absence of cytotoxic activity and the promotion of osteoblast proliferation. The titanium alloy coating was investigated indirectly using a fluorescent probe and directly by environmental scanning electron microscope (ESEM) analysis. Long-duration antibiotic release was demonstrated in vitro, and antibacterial efficacy against a Staphylococcus aureus culture was shown

A review of the role of lymphoma markers and occupational and environmental exposures

Immune deficiency and altered immunity are among the best characterized and strongest known risk factors of non-Hodgkin lymphomas (NHL). For instance, chronic inflammation or certain disturbances in the immune system are associated with an increased lymphoma risk. Occupational and environmental factors (i.e., dioxin) as well as lifestyle factors (i.e., obesity) may contribute to these risk factors. The precise role of these factors in the etiology of NHL, however, is still not entirely clear. Although the existing epidemiologic studies have not revealed consistent patterns of perturbations of the immune system by these factors, the findings might suggest an adverse impact on both the humoral and cell-mediated immune system