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Accelerating the wound healing of diabetes-impaired cutaneous tissue is still a challenge due to the aberrant cellular behavior, poor angiogenesis, and pathological micro-environment. Activation with growth factors and modulation of the redox micro-environment of the diabetic wound are considered to be effective strategies. Herein, we have described a highly sulfated heparin-like polysaccharide 2- N , 6- O -sulfated chitosan (26SCS)-doped poly(lactic- co -glycolic acid) scaffold (S-PLGA), which can achieve controlled and sustained release of heparin-binding epidermal growth factor (HB-EGF) owing to its affinity for heparin-binding growth factors. Interestingly, the antioxidant effect of 26SCS was confirmed and it was shown to have a strong scavenging activity towards superoxide radicals, a moderate scavenging activity towards hydroxyl radicals and a lower scavenging activity towards hydrogen peroxide. It also exhibited stronger protective effects in a human keratinocyte cell line (Ha-cat) against H 2 O 2 -induced oxidative damage. The Ha-cat cells cultured in the presence of the S-PLGA scaffold were significantly protected against oxidative stress during proliferation. In a full thickness excisional wound model of a diabetic rat, the wound treated with the HB-EGF-loaded S-PLGA scaffold was basically healed after 28 days. Conversely, the wounds in the other diabetic groups were not closed. The migration effect of the keratinocytes was enhanced by the 26SCS-induced sustainable release of HB-EGF and the scavenging of ROS which led to rapid re-epithelialization. Furthermore, histopathological evaluation demonstrated the positive effects on wound contraction, epithelial regeneration, and collagen deposition when treated with the HB-EGF loaded S-PLGA scaffold. These findings highlight that 26SCS may serve as a promising coagent for both controlled release of growth factors and alleviation of excessive ROS production, thus leading to increased regeneration of the diabetic wounds.

Potentiation effect on accelerating diabetic wound healing using 2-N,6-O-sulfated chitosan-doped PLGA scaffold