Thrombogenesis remains the primary failure of synthetic vascular grafts.Endothelial coverage is crucial to provide an antithrombogenic surface.However,most synthetic materials do not support cell adhesion,and transana...Thrombogenesis remains the primary failure of synthetic vascular grafts.Endothelial coverage is crucial to provide an antithrombogenic surface.However,most synthetic materials do not support cell adhesion,and transanastomotic endothelial migration is limited.Here,a surface modification strategy using fucoidan and topography was developed to enable fast in situ endothelialization of polyvinyl alcohol,which is not endothelial cell-adhesive.Among three different immobilization approaches compared,conjugation of aminated-fucoidan promoted endothelial monolayer formation while minimizing thrombogenicity in both in vitro platelet rich plasma testing and ex vivo non-human primate shunt assay.Screening of six topographical patterns showed that 2μm gratings increased endothelial cell migration without inducing inflammation responses of endothelial cells.Mechanistic studies demonstrated that fucoidan could attract fibronectin,enabling integrin binding and focal adhesion formation and activating focal adhesion kinase(FAK)signaling,and 2μm gratings further enhanced FAK-mediated cell migration.In a clinically relevant rabbit carotid artery end-to-side anastomosis model,60%in situ endothelialization was observed throughout the entire lumen of 1.7 mm inner diameter modified grafts,compared to 0%of unmodified graft,and the four-week graft patency also increased.This work presents a promising strategy to stimulate in situ endothelialization on synthetic materials for improving long-term performance.展开更多
基金This work was supported by the National Institutes of Health grants[NIH R01HL130274 and R01HL144113]NSERC-CREATE Training in Global Biomedical Technology Research and Innovation at the University of Waterloo[CREATE-509950-2018]+2 种基金Canada Foundation for Innovation(CFI35573)NSERC Research Tools and Instruments Fund(RTI-2018-00220)the Oregon National Primate Research Center NIH grant award[P51OD011092].
文摘Thrombogenesis remains the primary failure of synthetic vascular grafts.Endothelial coverage is crucial to provide an antithrombogenic surface.However,most synthetic materials do not support cell adhesion,and transanastomotic endothelial migration is limited.Here,a surface modification strategy using fucoidan and topography was developed to enable fast in situ endothelialization of polyvinyl alcohol,which is not endothelial cell-adhesive.Among three different immobilization approaches compared,conjugation of aminated-fucoidan promoted endothelial monolayer formation while minimizing thrombogenicity in both in vitro platelet rich plasma testing and ex vivo non-human primate shunt assay.Screening of six topographical patterns showed that 2μm gratings increased endothelial cell migration without inducing inflammation responses of endothelial cells.Mechanistic studies demonstrated that fucoidan could attract fibronectin,enabling integrin binding and focal adhesion formation and activating focal adhesion kinase(FAK)signaling,and 2μm gratings further enhanced FAK-mediated cell migration.In a clinically relevant rabbit carotid artery end-to-side anastomosis model,60%in situ endothelialization was observed throughout the entire lumen of 1.7 mm inner diameter modified grafts,compared to 0%of unmodified graft,and the four-week graft patency also increased.This work presents a promising strategy to stimulate in situ endothelialization on synthetic materials for improving long-term performance.
