Heparin-Modified Small-Diameter Nanofibrous Vascular Grafts
Department of Bioengineering, University of California, Berkeley, CA 94720USA.IEEE transactions on nanobioscience (Impact Factor: 2.31). 03/2012; 11(1):22-7. DOI: 10.1109/TNB.2012.2188926
Due to high incidence of vascular bypass procedures, an unmet need for suitable vessel replacements exists, especially for small-diameter vascular grafts. Here we produced 1-mm diameter vascular grafts with nanofibrous structure via electrospinning, and successfully modified the nanofibers by the conjugation of heparin using di-amino-poly(ethylene glycol) (PEG) as a linker. Antithrombogenic activity of these heparin-modified scaffolds was confirmed in vitro. After 1 month implantation using a rat common carotid artery bypass model, heparin-modified grafts exhibited 85.7% patency, versus 57.1% patency of PEGylated grafts and 42.9% patency of untreated grafts. Post-explant analysis of patent grafts showed complete endothelialization of the lumen and neovascularization around the graft. Smooth muscle cells were found in the surrounding neo-tissue. In addition, greater cell infiltration was observed in heparin-modified grafts. These findings suggest heparin modification may play multiple roles in the function and remodeling of nanofibrous vascular grafts, by preventing thrombosis and maintaining patency, and by promoting cell infiltration into the three-dimensional nanofibrous structure for remodeling.
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ABSTRACT: Tissue engineering of small-diameter blood vessels is still challenging because of restenosis and burst. To prevent thrombosis, rapid endothelialization along the lumen of grafts is intended, followed by proliferation of vascular smooth muscle cells (VSMCs) around the exterior for compliance. To this goal, two modified coaxial electrospinning techniques were developed to encapsulate vascular endothelial growth factor (VEGF) and platelet-derived growth factor-bb (PDGF), respectively, to regulate proliferation of vascular endothelial cells (VECs) and VSMCs. Release profiles, in vitro cell proliferation and in vivo implantation of double-layered electrospun membranes were investigated, and what made it special was the electrospun membranes were composed of chitosan hydrogel/poly(ethylene glycol)-b-poly(l-lactide-co-caprolactone) (PELCL) electrospun membrane loaded with VEGF as the inner layer and emulsion/PELCL electrospun membrane-loaded PDGF as the outer. It was found that dual-release of VEGF and PDGF could accelerate VEC proliferation in the first 6 days, and modulate slow VSMC proliferation in the initial 3 days whereas generate rapid proliferation after day 6, which is of great benefit to blood vessel regeneration. Four weeks of in vivo replacement of rabbit carotid artery demonstrated that VECs and VSMCs developed on the lumen and exterior of vascular grafts, respectively, and no thrombus or burst appeared. It was concluded that dual-delivery of VEGF and PDGF by the modified electrospun membranes could facilitate revascularization.