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One-Pot Covalent Grafting of Gelatin on Poly(Vinyl Alcohol) Hydrogel to Enhance Endothelialization and Hemocompatibility for Synthetic Vascular Graft Applications.

ABSTRACT: Cardiovascular diseases remain the leading cause of death worldwide. Patency rates of clinically-utilized small diameter synthetic vascular grafts such as Dacron® and expanded polytetrafluoroethylene (ePTFE) to treat cardiovascular disease are inadequate due to lack of endothelialization. Sodium trimetaphosphate (STMP) crosslinked PVA could be potentially employed as blood-compatible small diameter vascular graft for the treatment of cardiovascular disease. However, PVA severely lacks cell adhesion properties, and the efforts to endothelialize STMP-PVA have been insufficient to produce a functioning endothelium. To this end, we developed a one-pot method to conjugate cell-adhesive protein via hydroxyl-to-amine coupling using carbonyldiimidazole by targeting residual hydroxyl groups on crosslinked STMP-PVA hydrogel. Primary human umbilical vascular endothelial cells (HUVECs) demonstrated significantly improved cells adhesion, viability and spreading on modified PVA. Cells formed a confluent endothelial monolayer, and expressed vinculin focal adhesions, cell-cell junction protein zonula occludens 1 (ZO1), and vascular endothelial cadherin (VE-Cadherin). Extensive characterization of the blood-compatibility was performed on modified PVA hydrogel by examining platelet activation, platelet microparticle formation, platelet CD61 and CD62P expression, and thrombin generation, which showed that the modified PVA was blood-compatible. Additionally, grafts were tested under whole, flowing blood without any anticoagulants in a non-human primate, arteriovenous shunt model. No differences were seen in platelet or fibrin accumulation between the modified-PVA, unmodified PVA or clinical, ePTFE controls. This study presents a significant step in the modification of PVA for the development of next generation in situ endothelialized synthetic vascular grafts.

SUBMITTER: Rizwan M

PROVIDER: S-EPMC7351135 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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One-Pot Covalent Grafting of Gelatin on Poly(Vinyl Alcohol) Hydrogel to Enhance Endothelialization and Hemocompatibility for Synthetic Vascular Graft Applications.

Rizwan Muhammad M Yao Yuan Y Gorbet Maud B MB Tse John J Anderson Deirdre E J DEJ Hinds Monica T MT Yim Evelyn K F EKF

ACS applied bio materials 20191119 1

Cardiovascular diseases remain the leading cause of death worldwide. Patency rates of clinically-utilized small diameter synthetic vascular grafts such as Dacron® and expanded polytetrafluoroethylene (ePTFE) to treat cardiovascular disease are inadequate due to lack of endothelialization. Sodium trimetaphosphate (STMP) crosslinked PVA could be potentially employed as blood-compatible small diameter vascular graft for the treatment of cardiovascular disease. However, PVA severely lacks cell adhes ...[more]

PMID: 32656504

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Project description:Synthetic small diameter vascular grafts with mechanical properties of native arteries, resistance to thrombosis and capacity to stimulate in situ endothelialization are an unmet clinical need. Poly(vinyl alcohol) hydrogel (PVA) is an excellent candidate as a vascular graft due to its tunable mechanical properties. However, the hydrophilicity and bio-inertness of PVA prevents endothelialization in vivo. We hypothesize that the modification of PVA with biomolecules and topographies creates a hemocompatible environment that also enhances bioactivity. PVA modified with fibronectin, RGDS peptide, cyclicRGD (cRGD) peptide, or heparin provided cell-adhesion motifs, which were confirmed by detection of nitrogen through X-ray photoelectron spectroscopy. Protein- and peptide-modified surfaces showed a slight increase in human vascular endothelial cell proliferation over unmodified PVA. With the exception of fibronectin modification, modified surfaces showed in vitro hemocompatibility comparable with unmodified PVA. To further improve bioactivity, cRGD-PVA was combined with gratings and microlens topographies. Combined modifications of 2 ?m gratings or convex topography and cRGD significantly improved human vascular endothelial cell viability on PVA. In vitro hemocompatibility testing showed that topography on cRGD-PVA did not significantly trigger an increase of platelet adhesion or activation compared with unpatterned PVA. Using the more physiologically relevant ex vivo hemocompatibility testing, all PVA grafts tested showed similar platelet adhesion to ePTFE and significantly lower platelet accumulation compared to collagen-coated ePTFE grafts. The biochemical and topographical modification of PVA demonstrates excellent hemocompatibility with enhanced bioactivity of PVA, thus highlighting its potential as a vascular graft.New synthetic small diameter vascular grafts with mechanical properties, blood-clot resistance and endothelial lining mimicking native arteries remains an unresolved critical clinical need. We aim to achieve this by modifying the mechanically-tunable poly(vinyl alcohol) hydrogel (PVA) vascular graft with both biochemical and biophysical cues in the lumenal surface. PVA modified with cyclic RGD peptide and ordered micrometer-sized topography showed low platelet adhesion in both a rabbit in vitro and baboon ex vivo blood compatibility assay. Modified PVA also exhibited significant enhancement of human vascular endothelial cell viability and proliferation in vitro. The readily available, modified PVA grafts are the first to show biophysical and biochemical modification in a three-dimensional scaffold with hemocompatibility, biofunctionality and excellent potential for clinical application.

Dataset Information

One-Pot Covalent Grafting of Gelatin on Poly(Vinyl Alcohol) Hydrogel to Enhance Endothelialization and Hemocompatibility for Synthetic Vascular Graft Applications.

Publications

One-Pot Covalent Grafting of Gelatin on Poly(Vinyl Alcohol) Hydrogel to Enhance Endothelialization and Hemocompatibility for Synthetic Vascular Graft Applications.

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