Covalent linkage of sulfated hyaluronan to the collagen scaffold Mucograft® enhances scaffold stability and reduces proinflammatory macrophage activation in vivo

• Published in: Bioactive materials Vol. 8; pp. 420 - 434
• Main Authors: Al-Maawi, Sarah, Rother, Sandra, Halfter, Norbert, Fiebig, Karen M., Moritz, Juliane, Moeller, Stephanie, Schnabelrauch, Matthias, Kirkpatrick, Charles James, Sader, Robert, Wiesmann, Hans-Peter, Scharnweber, Dieter, Hintze, Vera, Ghanaati, Shahram
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.02.2022; KeAi Publishing; KeAi Communications Co., Ltd
• Subjects: Cellular reaction; Collagen; Multinucleated giant cells; Sulfated hyaluronan; Wound healing; Sulfated hyaluronan; Wound healing; Cellular reaction; Multinucleated giant cells; Collagen
• ISSN: 2452-199X; 2452-199X
• DOI: 10.1016/j.bioactmat.2021.06.008

Sulfated glycosaminoglycans (sGAG) show interaction with biological mediator proteins. Although collagen-based biomaterials are widely used in clinics, their combination with high-sulfated hyaluronan (sHA3) is unexplored. This study aims to functionalize a collagen-based scaffold (Mucograft®) with sHA3 via electrostatic (sHA3/PBS) or covalent binding to collagen fibrils (sHA3+EDC/NHS). Crosslinking without sHA3 was used as a control (EDC/NHS Ctrl). The properties of the sHA3-functionalized materials were characterized. In vitro growth factor and cytokine release after culturing with liquid platelet-rich fibrin was performed by means of ELISA. The cellular reaction to the biomaterials was analyzed in a subcutaneous rat model. The study revealed that covalent linking of sHA3 to collagen allowed only a marginal release of sHA3 over 28 days in contrast to electrostatically bound sHA3. sHA3+EDC/NHS scaffolds showed reduced vascular endothelial growth factor (VEGF), transforming growth factor beta 1 (TGF-β1) and enhanced interleukin-8 (IL-8) and epithelial growth factor (EGF) release in vitro compared to the other scaffolds. Both sHA3/PBS and EDC/NHS Ctrl scaffolds showed a high proinflammatory reaction (M1: CD-68+/CCR7+) and induced multinucleated giant cell (MNGC) formation in vivo. Only sHA3+EDC/NHS scaffolds reduced the proinflammatory macrophage M1 response and did not induce MNGC formation during the 30 days. SHA3+EDC/NHS scaffolds had a stable structure in vivo and showed sufficient integration into the implantation region after 30 days, whereas EDC/NHS Ctrl scaffolds underwent marked disintegration and lost their initial structure. In summary, functionalized collagen (sHA3+EDC/NHS) modulates the inflammatory response and is a promising biomaterial as a stable scaffold for full-thickness skin regeneration in the future. [Display omitted] •Covalent linking of high-sulfated hyaluronan (sHA3) to collagen allows a sustained release of sHA3.•Covalent linking of sHA3 to collagen modulates the release of growth factor and cytokines in vitro.•Covalent linking of sHA3 to collagen suppresses the induction of multinucleated giant cells in vivo.•Covalent linking of sHA3 to collagen reduces the proinflammatory macrophage M1 response in vivo.•Functionalized collagen with sHA3 is promising for full-thickness skin regeneration.