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Evaluation of Microscopic Structure-Function Relationships of PEGylated Small Intestinal Submucosa Vascular Grafts for Arteriovenous Connection Karen T. Valencia-Rivero, Juan C Cruz, Nicolle Wagner-Gutierrez, Antonio D'Amore, Maria C Miranda, Rocío López, Albert Guerrero, William R Wagner, Néstor F. Sandoval, and Juan C Briceño ACS Appl. Bio Mater., Just Accepted Manuscript • DOI: 10.1021/acsabm.9b00158 • Publication Date (Web): 31 May 2019 Downloaded from pubs.acs.org on July 23, 2019
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ACS Applied Bio Materials
Evaluation of Microscopic Structure-Function Relationships of PEGylated Small Intestinal Submucosa Vascular Grafts for Arteriovenous Connection Karen T. Valencia-Rivero1* Juan C. Cruz1 , Nicolle Wagner-Gutierrez1 , Antonio .
.
.
D’Amore2, 3, Maria C. Miranda4, Rocío López5, 6., Albert Guerrero4, William Wagner2, Néstor Sandoval4, Juan C. Briceño1
1.
Biomedical Engineering Department, Universidad de los Andes. Bogotá, Colombia.
2
McGowan Institute for Regenerative Medicine, University of Pittsburgh. Pittsburgh (PA)
USA. 3
Fondazione RiMED. Palermo, Italy.
4.
Fundación Cardioinfantil - Cardiovascular Institution. Bogotá, Colombia.
5.
Fundación Santa Fe de Bogotá. Bogotá, Colombia.
6.
School of Medicine, Universidad de los Andes. Bogotá, Colombia.
* Email address of the corresponding author:
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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 the clinical practice, upon implantation, synthetic vascular 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 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 equivalents [6 Eq] 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 2 ACS Paragon Plus Environment
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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.
KEYWORDS Small Intestinal Submucosa; Regenerative Vascular Grafts; Polyethylene Glycol; Microscopic Properties; Reduced Platelet Deposition; Swine Animal Model.
1. INTRODUCTION
When Kidney function is compromised, blood toxins are usually removed via hemodialysis, a renal replacement therapy in which patient blood circulates through a filter system to clean it by removing cellular waste1. During hemodialysis, inflow blood to the machine via an arterial line requires a continuous puncture of a vascular access, which is also needed to transfer clean blood from the machine back to the patient via a venous blood line. A vascular access is a surgical connection between a peripheral artery and an adjacent vein, made to progressively dilate during approximately 6 weeks. As a result, vein wall thickness increases, which is a pre-requisite for receiving arterialized blood from the hemodialysis machine2.
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A vascular access for hemodialysis can be built with the subcutaneous anastomosis of the native blood vessels of the patient (arteriovenous fistula, AVF) or by grafting a tube made of a prosthetic material, which is generally synthetic (synthetic vascular grafts)3. AVF is the gold standard procedure mainly because infections are reduced as no foreign materials are implanted, while expanded Polytetrafluoroethylene (ePTFE) grafts are the preferred choice among synthetic options because they can be used earlier than fistulas for hemodialysis4.
Upon implantation of AVF and ePTFE vascular grafts, the required graft-vein anastomosis might lead to hyperplasia of the venous intima, which in turn leads to stenosis and the eventual obstruction of the vascular access5. This has been attributed to turbulence at the anastomosis, and the compliance mismatch between the graft and the native blood vessels2,4,6. Stenosis and turbulence also increase the risk of blood clotting and therefore for thrombus formation. As a result, patency rates are significantly reduced in the long-term, which eventually results in the need of extra surgical interventions. This represents additional costs for the healthcare system7.
An alternative option to current synthetic vascular grafts is the use of biomaterials derived from extracellular matrices8,9. This approach has been explored to manufacture regenerative vascular grafts for the replacement or reparation of small blood vessels (
