Tissue-engineered vascular patches: comparative characteristics and preclinical test results in a sheep model

Abstract

Carotid endarterectomy (CEA) with patch angioplasty is the most effective treatment for carotid artery stenosis. However, the use of existing vascular patches is often associated with thrombosis, restenosis, calcification and other complications.Objective: to develop biodegradable patches for arterial reconstruction, containing vascular endothelial growth factor (VEGF) or arginyl-glycyl-aspartic acid (RGD), and comparatively evaluate their biocompatibility and efficacy in in vitro experiments and during preclinical trials in large laboratory animal models.Materials and methods. Biodegradable patches, made from a mixture of poly(3-hydroxybutyrate-co-3- hydroxyvalerate (PHBV) and poly(ε-caprolactone) (PCL), were fabricated by electrospinning and modified with VEGF or the peptide sequence RGD in different configurations. In in vitro experiments, the surface structure, physicomechanical and hemocompatibility properties were evaluated. In in vivo experiments, we evaluated the effectiveness of the developed vascular patches for 6 months after implantation into the carotid artery of 12 sheep. The quality of remodeling was assessed using histological and immunofluorescence studies of explanted specimens.Results. The PHBV/PCL/VEGF patches had physicomechanical characteristics closer to those of native vessels and their biofunctionalization method resulted in the smallest drop in strength characteristics compared with their unmodified PHBV/PCL counterparts. Modification with RGD peptides reduced the strength of the polymer patches by a factor of 2 without affecting their stress-strain behavior. Incorporation of VEGF into polymer fibers reduced platelet aggregation upon contact with the surface of the PHBV/PCL/VEGF patches and did not increase erythrocyte hemolysis. At month 6 of implantation into the carotid artery of sheep, the PHBV/PCL/ VEGF patches formed a complete newly formed vascular tissue without signs of associated inflammation and calcification. This indicates the high efficiency of the VEGF incorporated into the patch. In contrast, the patches modified with different configurations of RGD peptides combined the presence of neointimal hyperplasia and chronic granulomatous inflammation present in the patch wall and developed during bioresorption of the polymer scaffold.Conclusion. PHBV/PCL/VEGF patches have better biocompatibility and are more suitable for vascular wall reconstruction than PHBV/PCL/RGD patches.