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

Research output: Contribution to journalResearch articleContributedpeer-review


  • Sarah Al-Maawi - , University Hospital Frankfurt (Author)
  • Sandra Rother - , Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California at Irvine (Author)
  • Norbert Halfter - , Chair of Biomaterials (Author)
  • Karen M Fiebig - , NASU - Institute for Problems of Materials Science (Author)
  • Juliane Moritz - , Institute of Materials Science, Chair of Materials Technology (Author)
  • Stephanie Moeller - , Innovent e.V. (Author)
  • Matthias Schnabelrauch - , Innovent e.V. (Author)
  • Charles James Kirkpatrick - , University Hospital Frankfurt (Author)
  • Robert Sader - , University Hospital Frankfurt (Author)
  • Hans-Peter Wiesmann - , Chair of Biomaterials (Author)
  • Dieter Scharnweber - , Chair of Biomaterials (Author)
  • Vera Hintze - , Chair of Biomaterials (Author)
  • Shahram Ghanaati - , University Hospital Frankfurt (Author)


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.


Original languageEnglish
Pages (from-to)420-434
Number of pages15
JournalBioactive Materials
Publication statusPublished - Feb 2022

External IDs

PubMed 34541411
PubMedCentral PMC8429620
Scopus 85109396319
ORCID /0000-0002-5611-9903/work/142244056