Evaluation of in situ tissue-engineered arteriovenous grafts suitable for cannulation in a large animal model

The sustainability of vascular access for hemodialysis is limited by frequent interventions and the inability of synthetic grafts to self-heal. Tissue engineering offers a solution through biodegradable grafts that remodel into autologous tissue. Here we assess electrospun polycarbonate-bis urea (PC-BU) vascular scaffolds (6mm-inner-Ø), reinforced with 3D-printed polycaprolactone coils, in a goat model, and compared them to expanded polytetrafluoroethylene (ePTFE) controls. The tissue-engineered grafts were repeatedly cannulated starting two weeks after implantation and were evaluated using computed tomography and histological analyses. By 12 weeks, the PC-BU grafts remodel into autologous tissue while maintaining structural integrity, maintaining integrity without dilations, ruptures, or aneurysms. Cannulation does not interfere with scaffold degradation or neo-tissue formation. Although the patency rate is lower for the PC-BU grafts (50%) compared to ePTFE (100%), the engineered grafts exhibit a self-healing response not seen in ePTFE. These findings demonstrate the potential of PC-BU tissue-engineered grafts as healing, functional vascular access solutions for hemodialysis, supporting cannulation during tissue transformation.</p

Off-the-Shelf Synthetic Biodegradable Grafts Transform In Situ into a Living Arteriovenous Fistula in a Large Animal Model

Current vascular access options require frequent interventions. In situ tissue engineering (TE) may overcome these limitations by combining the initial success of synthetic grafts with long-term advantages of autologous vessels by using biodegradable grafts that transform into autologous vascular tissue at the site of implantation. Scaffolds (6 mm-Ø) made of supramolecular polycarbonate-bisurea (PC-BU), with a polycaprolactone (PCL) anti-kinking-coil, are implanted between the carotid artery and jugular vein in goats. A subset is bio-functionalized using bisurea-modified-Stromal cell-derived factor-1α (SDF1α) derived peptides and ePTFE grafts as controls. Grafts are explanted after 1 and 3 months, and evaluated for material degradation, tissue formation, compliance, and patency. At 3 months, the scaffold is resorbed and replaced by vascular neo-tissue, including elastin, contractile markers, and endothelial lining. No dilations, ruptures, or aneurysms are observed and grafts are successfully cannulated at termination. SDF-1α-peptide-biofunctionalization does not influence outcomes. Patency is lower in TE grafts (50%) compared to controls (100% patency), predominantly caused by intimal hyperplasia. Rapid remodeling of a synthetic, biodegradable vascular scaffold into a living, compliant arteriovenous fistula is demonstrated in a large animal model. Despite lower patency compared to ePTFE, transformation into autologous and compliant living tissue with self-healing capacity may have long-term advantages.</p

Vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic stress

The intermediate filament (IF) cytoskeleton has been proposed to regulate morphogenic processes by integrating the cell fate signaling machinery with mechanical cues. Signaling between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) through the Notch pathway regulates arterial remodeling in response to changes in blood flow. Here we show that the IF-protein vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic forces. Vimentin is important for Notch transactivation by ECs and vimentin knockout mice (VimKO) display disrupted VSMC differentiation and adverse remodeling in aortic explants and in vivo. Shear stress increases Jagged1 levels and Notch activation in a vimentin-dependent manner. Shear stress induces phosphorylation of vimentin at serine 38 and phosphorylated vimentin interacts with Jagged1 and increases Notch activation potential. Reduced Jagged1-Notch transactivation strength disrupts lateral signal induction through the arterial wall leading to adverse remodeling. Taken together we demonstrate that vimentin forms a central part of a mechanochemical transduction pathway that regulates multilayer communication and structural homeostasis of the arterial wall

Data underlying the publication "Vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic stress"

The data and resulting publication combine in vivo animal studies on mice, cell biological in vitro experiments and computational modeling to study the role of the intermediate filament protein vimentin as a mechanosensitive regulator of Notch signaling and arterial remodeling. The dataset consists of computational simulation, fluorescence-assisted cell sorting, immunofluorescence and histological staining, luciferase reporter assay, quantitative real-time polymerase chain reaction and Western blotting data