Metal complexes with linear and crosslinked polysaccharides as mediators of angiogenesis

Bioactive macromolecules resulting from chemical modification of hyaluronic acid (Hyal) have been designed to improve the compatibility of biomaterials used for cardiovascular prostheses. Hyal has been sulphated to obtain derivatives (HyalS) with a number of sulphate groups ranging from 1 to 4 per disaccharide unit. Hydrogels of Hyal have been obtained by cross-linking the free polysaccharide. An appropriate Hyal/cross-linking agent ratio has produced a hydrogel with a degree of crosslinking of 50%. In the present study, the ability to stimulate endothelial cell adhesion and migration was evaluated for free Hyal, HyalS3.5 and their complexes with Cu(II) and Zn(II) ions. The results revealed that Hyal and [Cu(OH)2HyalS3.5](4.5)ÿ induced cell adhesion, while [ZnHyalS3.5](2.5)ÿ and [Zn(OH)2HyalS3.5](4.5)ÿ inhibi- ted the process. The chemotactic activity of increasing concentrations of the above complexes was also evaluated, demonstrating that [Cu(OH)2HyalS3.5](4.5)ÿ complex at 1 mM concentration was the most active in inducing cell migration. These results were also confirmed by analys- ing cell migration in agarose. The 50% hydrogel bound Cu(II) and Zn(II) and the in vivo biocompatibility of the complexes was found to be good.