Modulating Expanded Polytetrafluoroethylene Vascular Graft Host Response via Citric Acid-Based Biodegradable Elastomers

Atherosclerotic vascular disease, in the form of coronary artery and peripheral vascular disease, remains the leading cause of mortality in the United States. For many patients, suitable vein autografts are not available. Synthetic grafts made from Dacron (polyethylene terephthalate) or expanded polytetrafluoroethylene (ePTFE) are mostly used in large-diameter (> 6 mm inner diameter) blood-vessel applications. However, their use in small-diameter blood vessels has been fraught with poor patency due to early graft occlusion from thrombosis. Surface-modification protocols mostly target ePTFE vascular grafts, the current standard-of-care, as their innate surface is thrombogenic and their intrinsic hydrophobicity can limit endothelium formation. Modifications to improve the thromboresistance of the graft have focused on the coating or immobilization of biomacromolecules or nondegradable polymers to promote endothelialization of the graft’s lumen. However, concerns regarding changes to the graft’s compliance, host responses to the coating material, transmission of pathogens, high costs, and long-term patency still remain. To date, no one has investigated the use of synthetic biodegradable polymers as a means to tissue-engineer a functional endothelium on ePTFE grafts. We demonstrate that the biodegradable elastomer poly(1,8-octanediol citrate) (POC) can confer improved biocompatibility characteristics on ePTFE vascular grafts without affecting graft compliance. The approach ultimately aims to improve early thromboresistance and perhaps inhibit neointimal hyperplasia by promoting POC-mediated mechanical interlocking between a newly formed endothelial layer and the underlying ePTFE fibrils and nodes. The POC synthesis and interfacial deposition methods presented herein are convenient and inexpensive, factors that are important to the widespread use and industrial scale-up for clinical application. POC prepolymer was synthesized via the polycondensation of citric acid and 1,8-octanediol as previously described and dissolved in ethanol for further use with the ePTFE grafts. Unlike other polycondensation reactions, which require high temperatures (normally, > 200 °C), catalysts or enzymes, and high vacuum, synthesis of POC can be conducted under relatively low temperatures (typically 60–80 °C, or as low as 37 °C, if necessary) without vacuum and catalysts. The time to achieve total degradation of POC, which may range from a few months to over a year, can be controlled with the degree of crosslinking via the extent of reaction, choice of diol, molar ratio of the diol to citric acid, and doping with hydrophilic crosslinking monomers such as Nmethyldiethanolamine and glycerol. POC’s modulus and elongation-at-break range from 0.5–11 MPa and 100–400 %, respectively, depending on the synthesis conditions used. A spin-shearing technique was developed to evenly coat the POC prepolymer onto the luminal surface of the ePTFE vascular grafts, effectively functionalizing the surface with carboxyl and hydroxyl functional groups. The POC-coated graft was post-polymerized at 80 °C for two days to create an elastomeric biodegradable polymer network on the ePTFE. The latter procedure is referred to as interfacial in situ polycondensation. POC modification of ePTFE (POC–ePTFE) significantly changed the surface energy of the ePTFE grafts without affecting graft compliance. The lumen of the graft was mostly covered with POC, > 95 % as assessed using scanning electron microscopy (SEM) and image-analysis software. Notably, the overall microarchitecture of the fibril and node network of ePTFE is preserved within the deposited POC layer (Fig. 1B). The compliance of POC–ePTFE grafts was not significantly different from that of control ePTFE grafts (Fig. 1C). This finding is due, in part, to the elastomeric nature of POC, which allows it to mobilize according to the expansion or contraction of the PTFE fibrils and nodes when the graft is exposed to pulsatile flow conditions. Surface Fourier transform infrared (FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), and contact-angle measurements further confirmed the morphological evidence for successful coating of the ePTFE graft (Fig. 1D–F). From the FTIR data, the broad peaks centered at 3475 and 3215 cm were assigned to the hydroxyl-group stretching vibration and mO–H of the carboxyl groups of POC. The peaks at 2925 and 2850 cm and the peaks within the range 1690–1750 cm in spectrum B shown in Figure 1D were assigned to the –CH2– and carbonyl (C O) groups of POC, respectively. XPS analysis (Fig. 1E) C O M M U N IC A IO N S