Evaluation of Microscopic Structure−Function Relationships of PEGylated Small Intestinal Submucosa Vascular Grafts for Arteriovenous Connection

Abstract

Vascular grafts are used as vascular access for hemodialysis, the most common renal replacement therapy to artificially clean blood waste after kidney malfunction. Despite that they are widely used in clinical practice, upon implantation, synthetic vasculars show complications such as thrombogenesis, reduced patency rates, low blood pressure, or even complete collapse. In this study, a C-shaped vascular graft was manufactured with small intestinal submucosa (SIS) and modified on the surface and the bulk of the material via conjugation of polyethylene glycol (PEG) to obtain a biocompatible and less thrombogenic vascular graft than the commercially available polytetrafluoroethylene (ePTFE) vascular grafts. Molecular weight and concentration of PEG molecules were systematically varied to gain insights into the underlying structure−function relationships. We analyzed the chemical, thermal, and mechanical properties of vascular grafts modified with 6 equiv of SIS-PEG 400 as well as cytotoxicity and in vitro platelet deposition. Immune response, patency rates, and extent of regeneration were also tested in vivo with the aid of swine animal models. Results showed that the conjugation levels achieved were sufficient to improve graft compliance, therefore approaching that of native vessels, while platelet deposition was altered leading to a 95% reduction compared with pristine SIS and 92% with respect to ePTFE. H&E staining on explanted samples corroborated SIS-PEG 400 biocompatibility and the ability to promote regeneration. The obtained results set solid foundations for the rational design and manufacture of a regenerative, small diameter vascular graft model and introduce an alternative to ePTFE vascular grafts for hemodialysis access.

Bioengineering and Biotechnology Approaches in Cardiovascular Regenerative Medicine, Volume II

“…In parallel with the development of scaffold optimization tools, equally important is a rich availability of scaffold fabrication techniques and biopolymer choices, both of which promote parametric control for optimizations. Some recent developments in the graft fabrication include: 1) Shortening the production time for cell sheet self-assembly method (von Bornstädt et al, 2018); 2) loading drugs, anti-thrombogenic or pro-regenerative molecules for electrospun grafts or 3D printed grafts Domínguez-Robles et al, 2021); 3) refining decellularization protocols for reduced immunological responses (Schneider et al, 2018;Valencia-Rivero et al, 2019;Kimicata et al, 2020;; 4) improving the precision of pore generation in scaffold (Zhen et al, 2021); 5) enhancing recellularization for allogenic or xenogenic decellularized grafts (Dahan et al, 2017;Fayon et al, 2021); 6) expediting degradation with scaffold composition (Fukunishi et al, 2021) or textile technique (Fukunishi et al, 2019) to enhance matrix remodeling; 7) mimicking the structure and/or composition of vascular ECM using electrochemical fabrication (Nguyen et al, 2018) or an automated technology combining dip-spinning with solution blow spinning (Akentjew et al, 2019); 8) creating patient-specific grafts ; and 9) hybrid approaches, for example, combining electrospinning with decellularized matrices (Gong et al, 2016;Ran et al, 2019;Wu et al, 2019;.…”

“…A vein fistula for dialysis access, for example, shows better primary patency than a polytetrafluoroethylene (PTFE) graft (Stegmayr et al, 2021). Similarly, for femoro-popliteal bypass, the 5-year patency rate of a vein graft is higher than a PTFE graft (van der Slegt et al, 2014). However, a quality vein suitable for grafting may be unavailable for many patients, particularly elders (Conte, 2012;AbuRahma, OPEN ACCESS EDITED BY 2018).…”

Strategies to counteract adverse remodeling of vascular graft: A 3D view of current graft innovations

“…In parallel with the development of scaffold optimization tools, equally important is a rich availability of scaffold fabrication techniques and biopolymer choices, both of which promote parametric control for optimizations. Some recent developments in the graft fabrication include: 1) Shortening the production time for cell sheet self-assembly method ( von Bornstädt et al, 2018 ); 2) loading drugs, anti-thrombogenic or pro-regenerative molecules for electrospun grafts or 3D printed grafts ( Zhang et al, 2019 ; Domínguez-Robles et al, 2021 ); 3) refining decellularization protocols for reduced immunological responses ( Schneider et al, 2018 ; Valencia-Rivero et al, 2019 ; Kimicata et al, 2020 ; Lopera Higuita et al, 2021 ); 4) improving the precision of pore generation in scaffold ( Zhen et al, 2021 ); 5) enhancing recellularization for allogenic or xenogenic decellularized grafts ( Dahan et al, 2017 ; Lin et al, 2019 ; Fayon et al, 2021 ); 6) expediting degradation with scaffold composition ( Fukunishi et al, 2021 ) or textile technique ( Fukunishi et al, 2019 ) to enhance matrix remodeling; 7) mimicking the structure and/or composition of vascular ECM using electrochemical fabrication ( Nguyen et al, 2018 ) or an automated technology combining dip-spinning with solution blow spinning ( Akentjew et al, 2019 ); 8) creating patient-specific grafts ( Fukunishi et al, 2017 ); and 9) hybrid approaches, for example, combining electrospinning with decellularized matrices ( Gong et al, 2016 ; Ran et al, 2019 ; Wu et al, 2019 ; Yang et al, 2019 ).…”

“…A vein fistula for dialysis access, for example, shows better primary patency than a polytetrafluoroethylene (PTFE) graft (Stegmayr et al, 2021). Similarly, for femoro-popliteal bypass, the 5-year patency rate of a vein graft is higher than a PTFE graft (van der Slegt et al, 2014). However, a quality vein suitable for grafting may be unavailable for many patients, particularly elders (Conte, 2012;AbuRahma, 2018).…”

Polyester urethane urea (PEUU) functionalization for enhanced anti-thrombotic performance: advancing regenerative cardiovascular devices through innovative surface modifications

“…Passive surface modifications, such as low-adherent topographies or PEGylation to improve hydrophilicity, can be employed to modify these processes. However, caution is necessary when considering these approaches for cardiovascular devices that require reendothelialization for optimal clinical outcomes ( Valencia-Rivero et al, 2019 ; Valencia-Rivero et al, 2019 ). Alternatively, active surface modification mainly focuses on surface functionalization with bioactive molecules that target thrombin generation and fibrin formation.…”