End-point immobilization of heparin on plasma-treated surface of electrospun polycarbonate-urethane vascular graft

Abstract

Small-diameter synthetic vascular grafts have high failure rate due to primarily surface thrombogenicity, and effective surface chemical modification is critical to maintain the patency of the grafts. In this study, we engineered a small-diameter, elastic synthetic vascular graft with off-the-shelf availability and anti-thrombogenic activity. Polycarbonate-urethane (PCU), was electrospun to produce nanofibrous grafts that closely mimicked a native blood vessel in terms of structural and mechanical strength. To overcome the difficulty of adding functional groups to PCU, we explored various surface modification methods, and determined that plasma treatment was the most effective method to modify the graft surface with functional amine groups, which were subsequently employed to conjugate heparin via end-point immobilization. In addition, we confirmed in vitro that the combination of plasma treatment and end-point immobilization of heparin exhibited the highest surface density and correspondingly the highest anti-thrombogenic activity of heparin molecules. Furthermore, from an in vivo study using a rat common carotid artery anastomosis model, we showed that plasma-heparin grafts had higher patency rate at 2 weeks and 4 weeks compared to plasma-control (untreated) grafts. More importantly, we observed a more complete endothelialization of the luminal surface with an aligned, well-organized monolayer of endothelial cells, as well as more extensive graft integration in terms of vascularization and cell infiltration from the surrounding tissue. This work demonstrates the feasibility of electrospinning PCU as synthetic elastic material to fabricate nanofibrous vascular grafts, as well as the potential to endow desired functionalization to the graft surface via plasma treatment for the conjugation of heparin or other bioactive molecules.

The regeneration of macro‐porous electrospun poly(ɛ‐caprolactone) vascular graft during long‐termin situimplantation

“…In addition, surface modification with bioactive molecules, such as SDF‐1 or heparin, is another alternative strategy to generate nonthrombogenic grafts. Several vascular scaffolds have demonstrated promise for clinical application by in vitro studies or short‐term in vivo studies (less than six months) . But some important challenges remain to be addressed before these materials can be used routinely for patient care, especially the potential adverse long‐term effects.…”

Implantation of VEGF‐functionalized cell‐free vascular grafts: regenerative and immunological response

“…Indeed, because platelets also carry the integrin α5β1 that binds the RGD domain, use of full‐length fibronectin presents the risk of homing throm‐bogenic cells to the graft lumen (29, 31). Furthermore, the use of the glycosaminoglycan heparin has been utilized in small animal models to prevent thrombosis (8, 32, 33) but has failed to prevent thrombosis in large animal models, such as sheep (34).…”

Electrospun Fibrous Architectures for Drug Delivery, Tissue Engineering and Cancer Therapy

“…Cardiovascular diseases, such as coronary artery and peripheral vascular diseases still remain as the prevalent cause of death due to the continued growing of aged population world widely. [31b,33a,72] Artificial vascular grafts to replace diseased or narrowed vessels have been recognized as the clinical focus owing to the limited donation of autologous vessels. Although commercial products such as Dacron and Teflon have been successfully applied as large diameter (>6 mm) vascular grafts with high blood flow, acute thrombus formation and intimal hyperplasia could be initiated in case of small diameter vascular grafts (SDVGs) (<6 mm), by the surface thrombogenicity and low compliance of Dacron and Teflon 177.…”

“…Surface modification, such as heparin immobilization, represents another crucial strategy to functionalize the tubular fibrous scaffolds for SDVGs regeneration. [33a,72,178] In the study of Yao et al,[33a] heparin was immobilized onto PLC/chitosan electrospun fibers through ionic bonding, resulting in stable release over 37 days to improve the hemocompatibility. When implanted in rat abdominal aorta for 1 month, the scaffolds showed well antithrombogenic effect and enhanced in situ endothelialization.…”