title: Early in-situ cellularization of a supramolecular vascular graft is modified by synthetic stromal cell-derived factor-1α derived peptides.
abstract: In an in-situ approach towards tissue engineered cardiovascular replacement grafts, cell-free scaffolds are implanted that engage in endogenous tissue formation. Bioactive molecules can be incorporated into such grafts to facilitate cellular recruitment. Stromal cell derived factor 1α (SDF1α) is a powerful chemoattractant of lymphocytes, monocytes and progenitor cells and plays an important role in cellular signaling and tissue repair. Short SDF1α-peptides derived from its receptor-activating domain are capable of activating the SDF1α-specific receptor CXCR4. Here, we show that SDF1α-derived peptides can be chemically modified with a supramolecular four-fold hydrogen bonding ureido-pyrimidinone (UPy) moiety, that allows for the convenient incorporation of the UPy-SDF1α-derived peptides into a UPy-modified polymer scaffold. We hypothesized that a UPy-modified material bioactivated with these UPy-SDF1α-derived peptides can retain and stimulate circulating cells in an anti-inflammatory, pro-tissue formation signaling environment. First, the early recruitment of human peripheral blood mononuclear cells to the scaffolds was analyzed in vitro in a custom-made mesofluidic device applying physiological pulsatile fluid flow. Preferential adhesion of lymphocytes with reduced expression of inflammatory factors TNFα, MCP1 and lymphocyte activation marker CD25 was found in the bioactivated scaffolds, indicating a reduction in inflammatory signaling. As a proof of concept, in-vivo implantation of the bioactivated scaffolds as rat abdominal aorta interposition grafts showed increased cellularity by CD68+ cells after 7 days. These results indicate that a completely synthetic, cell-free biomaterial can attract and stimulate specific leukocyte populations through supramolecular incorporation of short bioactive SDF1α derived peptides.
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, The Netherlands.
authors.forename: Dimitri E P
authors.initials: DE
authors.lastname: Muylaert
authors.affiliation: Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands; Department of Biomedical Engineering, Laboratory of Chemical Biology, Eindhoven University of Technology, Eindhoven, The Netherlands.
authors.forename: Geert C
authors.initials: GC
authors.lastname: van Almen
authors.affiliation: Department of Cardiothoracic Surgery, Academic Medical Center Amsterdam/Leiden University Medical Center, The Netherlands.
authors.forename: Hanna
authors.initials: H
authors.lastname: Talacua
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, The Netherlands.
authors.forename: Joost O
authors.initials: JO
authors.lastname: Fledderus
authors.affiliation: Department of Cardiothoracic Surgery, Academic Medical Center Amsterdam/Leiden University Medical Center, The Netherlands.
authors.forename: Jolanda
authors.initials: J
authors.lastname: Kluin
authors.affiliation: Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands; Department of Biomedical Engineering, Laboratory of Chemical Biology, Eindhoven University of Technology, Eindhoven, The Netherlands.
authors.forename: Simone I S
authors.initials: SI
authors.lastname: Hendrikse
authors.affiliation: Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands; Department of Chemical Engineering and Chemistry, Laboratory of Macromolecular and Organic Chemistry, Eindhoven University of Technology, Eindhoven, The Netherlands.
authors.forename: Joost L J
authors.initials: JL
authors.lastname: van Dongen
authors.affiliation: Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands; Department of Biomedical Engineering, Laboratory of Chemical Biology, Eindhoven University of Technology, Eindhoven, The Netherlands.
authors.forename: Eline
authors.initials: E
authors.lastname: Sijbesma
authors.affiliation: SupraPolix BV, Eindhoven, The Netherlands.
authors.forename: Anton W
authors.initials: AW
authors.lastname: Bosman
authors.affiliation: SupraPolix BV, Eindhoven, The Netherlands.
authors.forename: Tristan
authors.initials: T
authors.lastname: Mes
authors.affiliation: Department of Biomedical Engineering, Laboratory for Cell and Tissue Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.
authors.forename: Shraddha H
authors.initials: SH
authors.lastname: Thakkar
authors.affiliation: Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands; Department of Biomedical Engineering, Laboratory for Cell and Tissue Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.
authors.forename: Anthal I P M
authors.initials: AI
authors.lastname: Smits
authors.affiliation: Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands; Department of Biomedical Engineering, Laboratory for Cell and Tissue Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.
authors.forename: Carlijn V C
authors.initials: CV
authors.lastname: Bouten
authors.affiliation: Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands; Department of Biomedical Engineering, Laboratory of Chemical Biology, Eindhoven University of Technology, Eindhoven, The Netherlands; Department of Biomedical Engineering, Laboratory for Cell and Tissue Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands. Electronic address: p.y.w.dankers@tue.nl.
authors.forename: Patricia Y W
authors.initials: PY
authors.lastname: Dankers
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, The Netherlands.
authors.forename: Marianne C
authors.initials: MC
authors.lastname: Verhaar
mesh_terms: D001807:Blood Vessel Prosthesis; D054377:Chemokine CXCL12 / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D008855:Microscopy, Electron, Scanning; D010455:Peptides / Q000737:chemistry*; D059748:Proteolysis; D023822:Tissue Engineering
chemical_list: D054377:Chemokine CXCL12; D010455:Peptides
keywords: Bioactive scaffold; Cardiovascular tissue engineering; Cell free graft; SDF1a; Stromal cell derived factor; Supramolecular