Construction Of Sulfonated Hyaluronic Acid-based Hydrogels And Modulation Of Traumatic Inflammatory Microenvironment In Traumatized Surfaces

The skin helps the body fight off infection and injury.Skin wound healing is usually divided into four phases,and chronic wounds such as diabetes are in a constant inflammatory phase,which greatly prolongs the healing time and causes a heavy economic and medical burden.Heparin has the ability to regulate the wound microenvironment through the binding of certain cytokine binding domains,which can promote chronic wound healing.In order to clarify the binding mechanism,to further broaden the range of the material’s application and to produce a material with the same biological function as heparin,a structurally tunable sulphonated hyaluronic acid（s HHA）was selected as the backbone for the construction of hydrogels,which were applied to chronic wounds to investigate their effects on wound healing by modulating the inflammatory microenvironment of wounds.In the first part of the project,s HHA was synthesized by accessing different levels of sulphonated groups on hyaluronic acid,and a chemically cross-linked hydrogels was constructed with s HHA as the backbone and a four-armed polyethylene glycol（star-PEG）with terminal amino groups.The sulphonated hyaluronic acid hydrogel(s HHA_3.0 gel)with a high degree of sulfonation was screened in vitro and in vivo for better anti-inflammatory effects.When applied to diabetic wounds,s HHA_3.0 gel could reduce inflammation by means of a reduction in the microenvironmental levels of pro-inflammatory and chemokines,reducing M1-type macrophage polarization and recruitment,and also had excellent effects in promoting angiogenesis,re-epithelialization,collagen deposition,reducing wound ROS and wound healing.In the second part of the work,in combination with the inflammatory modulating effect of s HHA confirmed in the first part,the biological functions of different molecular weights of HA on inflammation were further constructed as high and low molecular weight sulfonated hyaluronic acid-based hydrogels,and the access to sulfonic acid groups on high molecular weight HA further amplified the biological functions of high molecular weight HA,which were validated in in vitro tumor necrosis factor-αand interferon-γbinding experiments and scratching experiments on human umbilical vein endothelial cells.In summary,the sulphonated hyaluronan-based hydrogels with different sulfonation degrees and molecular weights constructed in this thesis can promote wound healing by modulating the inflammatory microenvironment of traumatic surfaces.On the one hand,it was found that increasing the content of sulfonate groups and increasing the molecular amount of HA could increase the binding effect of the hydrogels on pro-inflammatory factors,elucidating the mechanism of action of glycosaminoglycan derivatives and extending the scope of application of the materials;On the other side,s HHA_3.0 gel was shown to be effective in promoting wound healing by modulating the diabetic wound inflammatory microenvironment.