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Hyaluronic acid biomaterials for perspective peripheral nerve regeneration

Ouasti, Sihem

[Thesis]. Manchester, UK: The University of Manchester; 2012.

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Abstract

This project focused on the design of a cellular scaffold applicable for the promotion of peripheral nerve regeneration. Firstly, we established a correlation between the organization of HA/PEG co-polymeric networks to their mechanical and degradability properties; cell adhesion was conferred to all gels by the incorporation of RGD peptides. Three families of hydrogels were produced using different procedures to permit an increasing physical incorporation of HA into a PEGDA-based network. From a comparative study of rheological properties and enzymatic degradability, co-networks obtained using thiolated HA as chain transfer agent during PEGDA photo-polymerization were selected for further biological investigations, aiming to link the cellular response of L929 murine fibroblasts (phenotype, proliferation rate, metabolic activity) to the composition and the consistency of selected hydrogels. Our findings showed that there is a clear relation between increasing hardness and increasing cell spreading/proliferation rate. This study illustrated the possibility to fine tune cell/material interactions with appropriate reactive processing techniques.As a spin-off of this study, we become interested in the interplay of cellular interactions in the use of materials that contain both HA and RGD peptides, which can bind at the same time to HA receptors such as CD44 and av integrins. We focused on soluble HA derivatives, with or without dandling RGD peptides. The kinetics and the mechanistic details of both HA and HA-RGD internalization were studied in a phagocytic model (J774.2 murine macrophages). HA-RGD showed a form of synergic binding to integrins and CD44 (HA receptor), whereas its uptake remained solely regulated by CD44 dwell-time on the cell membrane. This study demonstrated that the knowledge of the rate-determining steps of the uptake of a carrier is necessary for assessing its efficiency. In this case, the presence of multiple ligands on a carrier was beneficial in some respect, but may not be optimal to overcome internalization limitations that arise from the slow turnover of the determining receptor.Finally, we studied the relation between the regulation of the expression of CD44 / RHAMM (HA receptor mediated motility) and the motility of Schwann cells (peripheral glial cells) and stem cells differentiated into a glial phenotype. Rt-PCR and immuno-assay experiments suggested that RHAMM up-regulation is associated with glial differentiation and we speculate that in the future this HA receptor could be considered as a differentiation marker. We also illustrated the importance of HA / RHAMM interaction for the motility of glial cells. These results indicate the importance of HA in mediating glial cell function during peripheral nerve regeneration and have implications for therapeutic repair strategies.