Construction of tissue-engineered vascular grafts with high patency by mimicking immune stealth and blocking TGF-β mediated endothelial-to-mesenchymal transition

• Published in: Composites. Part B, Engineering Engineering, 2023-02, Vol.251, p.110487, Article 110487
• Main Authors: Fan, Yonghong, Pei, Juan, Li, Xinxin, Qin, Yinhua, Xu, Youqian, Ke, Ming, Zhang, Jie, Liu, Yong, Tan, Ju, Yang, Mingcan, Li, Gang, Li, Tianqing, Zhu, Chuhong
• Format: Article
• Language: English
• Subjects: CD47; Covalent organic frameworks; Endothelial-to-mesenchymal transition; TGF-β; Tissue-engineered vascular grafts
• ISSN: 1359-8368
• DOI: 10.1016/j.compositesb.2022.110487

Tissue-engineered vascular grafts (TEVGs) show great potential in clinics for treating vascular diseases. However, the complications including thrombosis, delayed endothelialization, and endothelial-to-mesenchymal transition (EndMT) induced pathological remodeling have been demonstrated to be the main cause of graft failure. Here, we have developed a multifunctional surface by immobilizing ALK5 inhibitor loaded covalent organic framework (COF) nanoparticles, recombinant CD47 protein, and vascular endothelial growth factor (VEGF). Such a surface can prevent thrombosis and stenosis in TEVGs. Immobilization of VEGF facilitated the recruitment of endothelial-forming cells to accelerate endothelialization. Grafting of CD47 endowed the TEVGs with stealth function to inhibit the adhesion and activation of platelets and macrophages, thereby suppressing thrombus formation and reducing the secretion of EndMT triggers (i.e. TNF-α and IL-1β). In addition, long-term in situ delivery of ALK5 inhibitor could block the TGF-β signaling pathway that mediated EndMT to prevent intima hyperplasia and endothelial dysfunction during graft remolding. This synergistic strategy is competent to support the formation of functional endothelium on the neo-intima, and has shown promising preliminary results in keeping the patency of TEVGs. [Display omitted] •Co-immobilization of CD47, VEGF, and ALK5 inhibitor loaded COF nanoparticles created a multifunctional surface on TEVGs.•Immobilization of CD47 possesses excellent ability to prevent the adhesion and activation of platelets and macrophages.•VEGF grafting accelerated endothelialization by homing endothelial forming cells.•In situ delivery of ALK5 inhibitor prevented the EndMT induced pathological remodeling of the TEVGs.•The TEVGs has high patency without thrombosis and stenosis.