Acta Biomaterialia 10 (2014) 2739–2749
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Acta Biomaterialia journal homepage: www.elsevier.com/locate/actabiomat
Effect of sustained heparin release from PCL/chitosan hybrid small-diameter vascular grafts on anti-thrombogenic property and endothelialization Yao Yao a,c,1, Jianing Wang a,1, Yun Cui a, Rong Xu b, Zhihong Wang a, Ju Zhang b, Kai Wang a, Yuejie Li b, Qiang Zhao a,⇑, Deling Kong a,b a State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials (Ministry of Education), College of Life Sciences, Nankai University, Tianjin 300071, People’s Republic of China b Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science, Tianjin 300192, People’s Republic of China c Center for Advanced Materials and Biotechnology, Research Institute of Tsinghua University in Shenzhen, Shenzhen 518057, People’s Republic of China
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Article history: Received 30 August 2013 Received in revised form 19 February 2014 Accepted 24 February 2014 Available online 4 March 2014 Keywords: Vascular grafts Heparin Anti-thrombogenic property Endothelialization
a b s t r a c t Thrombus formation and subsequent occlusion are the main reasons for the failure of small-diameter vascular grafts. In this study, a hybrid small-diameter vascular graft was developed from synthetic polymer poly(e-caprolactone) (PCL) and natural polymer chitosan (CS) by the co-electrospinning technique. Heparin was immobilized on the grafts through ionic bonding between heparin and CS fibers. The immobilization was relatively stable, and heparin could continuously release from the grafts for more than 1 month. Heparin functionalization evidently improved the hemocompatibility of the PCL/CS vascular grafts, which was illustrated by the reduced platelet adhesion and prolonged coagulation time (activated partial thromboplastin time, prothrombin time and thromboplastin time) as shown in the human plasma assay, and was further confirmed by the ex vivo arteriovenous shunt experiment. In vitro cell proliferation assay showed that heparin can promote the growth of human umbilical vein endothelial cells, while moderately inhibiting the proliferation of vascular smooth muscle cells, a main factor for neointimal hyperplasia. Implantation in rat abdominal aorta was performed for 1 month. Results indicate that sustained release of heparin provided optimal anti-thrombogenic effect by reducing thrombus formation and maintaining the patency. Furthermore, heparin functionalization also enhanced in situ endothelialization, thereby preventing the occurrence of restenosis. In conclusion, it provides a facile and useful technique for the development of heparinized medical devices, including vascular grafts. Ó 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
1. Introduction Nowadays, vascular diseases (including cardiovascular, peripheral blood vessels) seriously threaten the health of mankind. In clinic, vascular transplantation using autografts is an effective strategy and has been accepted as the ‘‘gold standard’’. But this strategy has often been limited by the availability or shortage of donors. Therefore, there is an urgent demand for artificial grafts as substitutes [1]. Although some artificial vascular grafts have achieved success in clinical application, products with small diameters (
Contents lists available at ScienceDirect
Acta Biomaterialia journal homepage: www.elsevier.com/locate/actabiomat
Effect of sustained heparin release from PCL/chitosan hybrid small-diameter vascular grafts on anti-thrombogenic property and endothelialization Yao Yao a,c,1, Jianing Wang a,1, Yun Cui a, Rong Xu b, Zhihong Wang a, Ju Zhang b, Kai Wang a, Yuejie Li b, Qiang Zhao a,⇑, Deling Kong a,b a State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials (Ministry of Education), College of Life Sciences, Nankai University, Tianjin 300071, People’s Republic of China b Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science, Tianjin 300192, People’s Republic of China c Center for Advanced Materials and Biotechnology, Research Institute of Tsinghua University in Shenzhen, Shenzhen 518057, People’s Republic of China
a r t i c l e
i n f o
Article history: Received 30 August 2013 Received in revised form 19 February 2014 Accepted 24 February 2014 Available online 4 March 2014 Keywords: Vascular grafts Heparin Anti-thrombogenic property Endothelialization
a b s t r a c t Thrombus formation and subsequent occlusion are the main reasons for the failure of small-diameter vascular grafts. In this study, a hybrid small-diameter vascular graft was developed from synthetic polymer poly(e-caprolactone) (PCL) and natural polymer chitosan (CS) by the co-electrospinning technique. Heparin was immobilized on the grafts through ionic bonding between heparin and CS fibers. The immobilization was relatively stable, and heparin could continuously release from the grafts for more than 1 month. Heparin functionalization evidently improved the hemocompatibility of the PCL/CS vascular grafts, which was illustrated by the reduced platelet adhesion and prolonged coagulation time (activated partial thromboplastin time, prothrombin time and thromboplastin time) as shown in the human plasma assay, and was further confirmed by the ex vivo arteriovenous shunt experiment. In vitro cell proliferation assay showed that heparin can promote the growth of human umbilical vein endothelial cells, while moderately inhibiting the proliferation of vascular smooth muscle cells, a main factor for neointimal hyperplasia. Implantation in rat abdominal aorta was performed for 1 month. Results indicate that sustained release of heparin provided optimal anti-thrombogenic effect by reducing thrombus formation and maintaining the patency. Furthermore, heparin functionalization also enhanced in situ endothelialization, thereby preventing the occurrence of restenosis. In conclusion, it provides a facile and useful technique for the development of heparinized medical devices, including vascular grafts. Ó 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
1. Introduction Nowadays, vascular diseases (including cardiovascular, peripheral blood vessels) seriously threaten the health of mankind. In clinic, vascular transplantation using autografts is an effective strategy and has been accepted as the ‘‘gold standard’’. But this strategy has often been limited by the availability or shortage of donors. Therefore, there is an urgent demand for artificial grafts as substitutes [1]. Although some artificial vascular grafts have achieved success in clinical application, products with small diameters (
