Application of Heparin/Collagen‐REDV Selective Active Interface on ePTFE Films to Enhance Endothelialization and Anticoagulation

Abstract

Expanded polytetrafluoroethylene (ePTFE) prosthetic valves have been widely used in clinical applications in Asian countries. However, these valves still have limits with regard to thrombosis, neointimal hyperplasia, restenosis, and valvar vegetation. The achievement of in situ endothelialization on implant materials is a promising way to overcome those limits. Here, heparin/collagen multilayers were fabricated on ePTFE films via a layer-by-layer (LBL) self-assembly technique, and then, the endothelial cell (EC) adhesive peptide sequence Arg-Glu-Asp-Val (REDV) was immobilized on the multilayers. After modification with the heparin/collagen multilayers with or without REDV peptide, less platelet activation and aggregation were observed, the blood coagulation time was increased, and the hemolysis rate was decreased compared to that on pristine ePTFE films. The REDV-functionalized ePTFE films positively impacted early EC adhesion, later cell proliferation and cell activity. The EC barrier was confirmed to be successfully achieved on the functionalized ePTFE film surface in vitro. The successful assembly of the REDV-functionalized heparin/collagen multilayer on ePTFE films improved the blood compatibility, anticoagulant properties, and cell compatibility of the films in vitro, and thus, represents a candidate approach for applications requiring quick in situ endothelialization in vivo.

Surface modification of polyvinyl alcohol (PVA)/polyacrylamide (PAAm) hydrogels with polydopamine and REDV for improved applicability

“…PDA has a strong adhesive property because of its rich amino and phenol hydroxyl groups, and its positive charge and specific domains improve focal adhesion site formation and cells adhesion; native serum proteins can also interact with adhesion receptors on a cells membrane and be absorbed on the dopamine surface . The cells proliferation of the hydrogels grafted with REDV was significantly higher than that of the hydrogels coated with dopamine, because REDV is a tetrapeptide found in fibronectin and can be specifically recognized and bound by receptors on the cytomembrane to benefit cells adhesion, notably in endothelial cells . Therefore, REDV coating is a promising method to promote endothelial cells adhesion on a vascular graft …”

“…42,46 The cells proliferation of the hydrogels grafted with REDV was significantly higher than that of the hydrogels coated with dopamine, because REDV is a tetrapeptide found in fibronectin and can be specifically recognized and bound by receptors on the cytomembrane to benefit cells adhesion, 31 notably in endothelial cells. 13 Therefore, REDV coating is a promising method to promote endothelial cells adhesion on a vascular graft. 54 A CCK-8 assay was conducted to quantitatively investigate the viability and proliferation of PIECs on the hydrogels.…”

“…Synthetic vascular grafts based on various polymers, such as polyethylene terephthalate (PET, Dacron®) and expanded polytetrafluoroethylene (ePTFE, Gore‐Tex®), are suitable alternatives widely used to treat large‐diameter blood vessel diseases (inner diameter > 6 mm) . However, their high thrombogenicity and poor elastic properties limit their further application in microvascular surgeries . Small‐diameter vascular grafts based on PET and ePTFE tend to induce a series of complications, such as thrombosis and intimal hyperplasia, because of hemodynamic differences between large and small blood vessels .…”

“…Inseong et al utilized PDA as an adaptor to graft heparin onto polyurethane substrates, leading to the enhancement of blood compatibility. REDV tetrapeptides have been commonly used as ligands to capture endothelial cells (ECs) for rapid endothelialization, because they can be recognized by α4β1 integrin receptors expressed almost exclusively on the cytomembrane of ECs and selectively enhance the attachment and migration of ECs over that of smooth muscle cells (SMCs) and platelets, which are required for vascular graft regeneration . Therefore, the goal of endothelialization can be achieved as the REDV tetrapeptides are grafted on a small‐diameter vascular graft without SMCs excessive proliferation.…”

“…[4][5][6][7][8] However, their high thrombogenicity and poor elastic properties limit their further application in microvascular surgeries. [9][10][11][12][13] Small-diameter vascular grafts based on PET and ePTFE tend to induce a series of complications, such as thrombosis and intimal hyperplasia, because of hemodynamic differences between large and small blood vessels. 14 One of the effective approaches to prevent thrombosis and maintain a high patency is to quickly regenerate an endothelium on the inner surface of the vascular prosthesis in vivo in a manner similar to that of native blood vessels.…”