In situ blood vessel regeneration using neuropeptide substance P-conjugated small-diameter vascular grafts

In situ blood vessel regeneration through host stem/progenitor cell mobilization may hold great promise for vascular reconstruction. Neuropeptide substance P (SP) has been shown to accelerate tissue repair by endogenous cell mobilization and recruitment. This study was aimed to evaluate the vascular regeneration potential of SP and heparin co-tethered vascular grafts. Polycaprolactone (PCL), PCL/SP-conjugated poly(L-lactide-co-ε-caprolactone) (PLCL-SP) (SP), and PCL/PLCL-SP/heparin-conjugated PLCL (Hep/SP) vascular grafts were implanted as rat abdominal aorta substitutes for up to 2 weeks and 4 weeks. Ex vivo results delineate that heparin can improve the hemocompatibility and SP can recruit mesenchymal stem cells. Histological and immunohistochemical staining reveal higher cellular infiltration and homogeneous cell distribution in SP and Hep/SP grafts than that of the control grafts. At 4 weeks, SP and Hep/SP grafts show the presence of cobblestone-like cells on the luminal side, whereas the surface of PCL grafts remains bare. Immunoflourescence staining using von Willibrand factor (vWF) antibody shows improved endothelialization in SP and Hep/SP grafts compared with the PCL grafts. SP and Hep/SP grafts also exhibit more numbers of α-smooth muscle actin-positive cells and laminin⁺ blood vessels than that of the control group. Evaluation of inflammatory response reveals that three groups did not differ in terms of the numbers of CD68⁺ macrophages, whereas SP and Hep/SP grafts show higher numbers of CD206⁺ macrophages. These results indicate that SP can induce endogenous tissue regeneration in cell-free grafts, which may be of great interest for regenerative medicine and tissue engineering applications. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1669-1683, 2019.