Antithrombogenic modification of small-diameter microfibrous vascular grafts.

OBJECTIVE: To develop small-diameter vascular grafts with a microstructure similar to native matrix fibers and with chemically modified microfibers to prevent thrombosis. METHODS AND RESULTS: Microfibrous vascular grafts (1-mm internal diameter) were fabricated by electrospinning, and hirudin was conjugated to the poly (L-lactic acid) microfibers through an intermediate linker of poly(ethylene glycol). The modified microfibrous vascular grafts were able to reduce platelet adhesion/aggregation onto microfibrous scaffolds, and immobilized hirudin suppressed thrombin activity that may interact with the scaffolds. This 2-pronged approach to modify microfibrous vascular graft showed significantly improved patency (from 50% to 83%) and facilitated endothelialization, and the microfibrous structure of the vascular grafts allowed efficient graft remodeling and integration, with the improvement of mechanical property (elastic modulus) from 3.5 to 11.1 MPa after 6 months of implantation. CONCLUSIONS: Microfibrous vascular grafts with antithrombogenic microfibers can be used as small-diameter grafts, with excellent patency and remodeling capability.

Heparin-modified small-diameter nanofibrous vascular grafts.

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.

Preclinical results of a prosthetic, early-stick graft with functional endothelium.

PURPOSE: The purpose of this study was to evaluate the NanoVasc Vascular Graft in comparison with a marketed expanded polytetrafluoroethylene (ePTFE) graft, both in vitro and in vivo. The graft was evaluated for use as both a bypass and arteriovenous (AV) access graft. Early-stick capabilities and patency were the primary end points evaluated. METHODS: Third party, independent laboratories completed mechanical testing, biocompatibility, and preclinical data collection. An ovine carotid artery interposition model and a canine femoral AV access model were used to evaluate 5-mm and 6-mm internal diameter sizes, respectively. RESULTS: There was no statistical difference in either model between the NanoVasc and ePTFE grafts with respect to patency. Time to hemostasis after cannulation with a 16-gauge needle was achieved ~10 times faster with the NanoVasc graft (mean time 27 seconds) compared with ePTFE. Histological analysis demonstrated functional endothelialization (nitric oxide expression), positive wound healing (cellular infiltration into the wall of the graft), and hemocompatibility of the NanoVasc graft. CONCLUSIONS: The NanoVasc Vascular Graft is a strong candidate as a bypass and AV access graft. Its early-stick capabilities and patency rates are an attractive feature in comparison with current AV access grafts.

Antithrombogenic property of bone marrow mesenchymal stem cells in nanofibrous vascular grafts.

Nanostructured biomaterials have tremendous potential for tissue engineering. However, the performance and integration of the nanomaterials in vivo are not well understood. A challenge in vascular tissue engineering is to develop optimal scaffolds and establish expandable cell sources for the construction of tissue-engineered vascular grafts that are nonthrombogenic and have long-term patency. Here, we used tissue-engineered vascular grafts as a model to demonstrate the potential of combining nanofibrous scaffolds and bone marrow mesenchymal stem cells (MSCs) for vascular tissue engineering. Biodegradable nanofibrous scaffolds with aligned nanofibers were used to mimic native collagen fibrils to guide cell organization in vascular grafts. The results from artery bypass experiments showed that nanofibrous scaffolds allowed efficient infiltration of vascular cells and matrix remodeling. Acellular grafts (without MSCs) resulted in significant intimal thickening, whereas cellular grafts (with MSCs) had excellent long-term patency and exhibited well organized layers of endothelial cells (ECs) and smooth muscle cells (SMCs), as in native arteries. Short-term experiments showed that nanofibrous scaffolds alone induced platelet adhesion and thrombus formation, which was suppressed by MSC seeding. In addition, MSCs, as ECs, resisted platelet adhesion in vitro, which depended on cell-surface heparan sulfate proteoglycans. These data, together with the observation on the short-term engraftment of MSCs, suggest that the long-term patency of cellular grafts may be attributed to the antithrombogenic property of MSCs. These results demonstrate several favorable characteristics of nanofibrous scaffolds, the excellent patency of small-diameter nanofibrous vascular grafts, and the unique antithrombogenic property of MSCs.