Bilateral Arteriovenous Shunts as a Method for Evaluating Tissue-Engineered Vascular Grafts in Large Animal Models

Abstract

There remains a need for large animal models to evaluate tissue-engineered vascular grafts (TEVGs) under arterial pressure to provide preclinical data for future potential human clinical trials. We present a comprehensive method for the interrogation of TEVGs, using an ovine bilateral arteriovenous (AV) shunt implantation model. Our results demonstrate that this method can be performed safely without complications, specifically acute heart failure, steal syndrome, and hypoxic brain injury, and it is a viable experimental paradigm. Our method allows for a non-invasive evaluation of TEVGs in terms of graft flow, graft diameter, and graft patency, while also allowing for graft needle puncture under ultrasound guidance. In addition, traditional pathological analysis, histology, and immunohistochemistry may be performed with the contralateral side providing paired control data to eliminate inter-subject variability while reducing the total number of animals. Further, we present a review of existing literature of preclinical evaluation of TEVGs in large animal models as AV conduits.

Concise Review: Patency of Small-Diameter Tissue-Engineered Vascular Grafts: A Meta-Analysis of Preclinical Trials

“…S1). Exclusion of duplicates and then systematic screening of title and abstract using the Covidence platform revealed 321 studies, which was finally limited by thorough text reading to 68 studies based on inclusion criteria . These studies represented a total of 873 grafts: 258 occluded and 615 patent grafts at the end of the evaluation period.…”

“…Most grafts, however, were evaluated in the time frame 1 day to 6 months (736 grafts). The median TEVG patency was 83% (n = 873) for a median follow-up time of 56 days (95% confidence interval: [42,60]).…”

Current Strategies for the Manufacture of Small Size Tissue Engineering Vascular Grafts

“…Electrospinning microfabrication technique is often used to generate tubular structures composed of nanofibers from different polymers. Composite scaffolds made of PCL/poly(ethylene oxide) (Wang et al, 2016 ) and PCL/PLGA (Ong et al, 2017 ) have been tested in animal models with the later acellular graft having been evaluated in an ovine bilateral arteriovenous shunt model. Such a model showed good results in term of patency (66%) and endothelialization of the lumen after 4 weeks of implantation, but the graft eventually dilated as a consequence of inadequate elastin content (Ong et al, 2017 ).…”

A Novel Hybrid Silk Fibroin/Polyurethane Arteriovenous Graft for Hemodialysis: Proof‐of‐Concept Animal Study in an Ovine Model

“…Notwithstanding that a direct comparison with commercially available arteriovenous grafts was not performed in this study, our finding is particularly significant considering that traditional 6 mm-diameter ePTFE grafts used as hemodialysis vascular accesses typically fail due to aggressive formation of intimal hyperplasia, and consequent stenosis with patency loss, at the venous anastomosis. [13,17] To address this critical aspect of arteriovenous shunting, several animal models have been developed over the last thirty years, [14,15] confirming that the primary unassisted patency of standard (5-6 mm in diameter) ePTFE grafts does not exceed 25% at 12 weeks in sheep [12,19] whereas secondary patency is approximately 67%. [20] In our study, deposition of endoluminal matrix of fibrotic and thrombotic origin was observed from day 30 to the end of the study along the graft length ( Figure 6; Figure S3, Supporting Information); however, this phenomenon, more accentuated close to the anastomoses (G1, G4, V2) than in the mid-graft region (G2-G3), did not result in a significant endoluminal stenosiswhose values stabilized at 25.06 ± 11.61% in V2 at 90 days-nor in a functional impairment, as confirmed by manual and ultrasound evaluation.…”

“…To address this critical aspect of arteriovenous shunting, several animal models have been developed over the last thirty years, [ 14,15 ] confirming that the primary unassisted patency of standard (5–6 mm in diameter) ePTFE grafts does not exceed 25% at 12 weeks in sheep [ 12,19 ] whereas secondary patency is approximately 67%. [ 20 ]…”