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.

Improving in vivo outcomes of decellularized vascular grafts via incorporation of a novel extracellular matrix

“…While these cells do not typically constitute a large portion of the media in healthy vasculature, there presence is not necessarily problematic. In fact, some researchers purposefully recruit CD68 + monocytes using bone marrow mononuclear cells or a stromal cell-derived factor 1α in grafts in order to take advantage of their ability to induce SMC and EC incorporation in the graft [48,49]. Therefore, it may be advantageous to have a certain level of immune cell recruitment to the graft.…”

Conjugation with RGD Peptides and Incorporation of Vascular Endothelial Growth Factor Are Equally Efficient for Biofunctionalization of Tissue-Engineered Vascular Grafts

“…The use of either RGD peptides or VEGF to enhance the biocompatibility of polymers is not novel [34]. However, to the best of our knowledge, nobody has compared these two biofunctionalization approaches in the same setting (e.g., in a rat abdominal aorta replacement model).…”

Quickening: Translational design of resorbable synthetic vascular grafts

“…(118) Some grafts were spun from pure PLCL-UPy, whereas some had UPy-conjugated fragments of SDF-1α added. UPy dimerizes with a free energy of 44–50 kJ/mol.…”