Thrombosis of synthetic vascular grafts is a major problem with current grafts that necessitates prophylaxis, can lead to loss of patency with an attendant need for repeat surgery, and comes with a high risk of limb loss. The applicant proposes to develop thromboresistant extended polytetrafluoroethylene (ePTFE) vascular grafts that use an absorbed coating of heparin to control acute and subacute thrombosis, and also incorporates a bioactive peptidomimetic to encourage endothelialization of the vascular graft surface to reduce chronic loss of patency. The applicant builds on a platform of in vitro and in vivo studies indicating that the adsorbed heparin coating provides thromboresistance for up to 30 days. The adsorbed heparin coating is a dipcoating and can be easily applied to grafts in a manufacturing setting. To this, the applicant will bring a unique series of peptidomimetics that it has separately developed. The peptidomimetics have been designed to complex to heparin and through that interaction provide a facile manufacturing mode. The applicant will use a series of in vitro and in vivo tests to evaluate the peptidomimetic that provides the highest level of graft endothelialization. Studies will also be conducted to establish if the peptide/heparin-coated graft can withstand sterilization with ethylene oxide, the preferred sterilization route for ePTFE. It is expected that Phase I studies will lead to the selection of a peptidomimetic(s) to be used in large animal studies of Phase II with the goal of providing durable thromboresistance over a protracted period of time with concomitant endothelialization of the graft surface.
