Potential of Heparan Sulphate Mimetics Integrated Into Collagen Scaffolds for Enhanced Skin Wound Healing

Optimal healing of full-thickness skin wounds remains a clinical challenge. While current skin substitutes aid burn wound management, there is still a need to effectively minimize scarring. Therefore, we developed type I collagen scaffolds with covalently bound ReGeneraTing Agent (RGTA) OTR4120 (OTR), a synthetic heparan sulphate analogue resistant to glycanase degradation (Col I + OTR). To further stimulate skin regeneration, collagen scaffolds with and without OTR4120 were subsequently loaded with sonic hedgehog (SHH), a key effector molecule in embryogenesis. The presence of OTR4120 and SHH in scaffolds was biochemically and histologically confirmed after crosslinking and sterilization. SHH was found deeper into collagen scaffolds in the presence of OTR4120. Addition of SHH to scaffolds showed lower expression of M1-like cell surface markers, while Col I + OTR significantly enhanced IL-10 production. The potential of OTR4120 in wound healing was further evaluated in vivo using a rat full-thickness wound model over 28 days. By day 14, macroscopic images revealed that OTR-treated wounds better maintained the original wound shape. Histological analysis showed increased blood vessel formation, fewer scaffold remnants and more contiguous sebaceous glands in the granulation tissue with Col I + OTR scaffolds. This study demonstrates that OTR4120 could be a promising addition to acellular skin substitutes for improving acute wound healing.