Next-Generation Biomaterials for Wound Healing: Development and Evaluation of Collagen Scaffolds Functionalized with a Heparan Sulfate Mimic and Fibroblast Growth Factor 2

Fibrosis after full-thickness wound healing-especially after severe burn wounds-remains a clinically relevant problem. Biomaterials that mimic the lost dermal extracellular matrix have shown promise but cannot completely prevent scar formation. We present a novel approach where porous type I collagen scaffolds were covalently functionalized with ReGeneRating Agent (RGTA^®) OTR4120. RGTA^® is a glycanase-resistant heparan sulfate mimetic that promotes regeneration when applied topically to chronic wounds. OTR4120 is able to capture fibroblast growth factor 2 (FGF-2), a heparan/heparin-binding growth factor that inhibits the activity of fibrosis-driving myofibroblasts. Scaffolds with various concentrations and distributions of OTR4120 were produced. When loaded with FGF-2, collagen-OTR4120 scaffolds demonstrated sustained release of FGF-2 compared to collagen-heparin scaffolds. Their anti-fibrotic potential was investigated in vitro by seeding primary human dermal fibroblasts on the scaffolds followed by stimulation with transforming growth factor β1 (TGF-β1) to induce myofibroblast differentiation. Collagen-OTR4120(-FGF-2) scaffolds diminished the gene expression levels of several myofibroblast markers. In absence of FGF-2 the collagen-OTR4120 scaffolds displayed an inherent anti-fibrotic effect, as the expression of two fibrotic markers (TGF-β1 and type I collagen) was diminished. This work highlights the potential of collagen-OTR4120 scaffolds as biomaterials to improve skin wound healing.