^{Six-Year-Old Sheep as a Clinically Relevant Large Animal Model for Aortic Valve Replacement Using Tissue-Engineered Grafts Based on Decellularized Allogenic Matrix}

Abstract

Tissue-engineered (TE) grafts based on decellularized grafts have shown very promising results in preclinical and clinical studies. However, in animal models valves have either been tested in juvenile models or in the clinically less relevant pulmonary valve position. In this study, we tested the grafts in the aortic valve (AV) position of 6-year-old sheep, as geriatric patients in need of an AV substitute due to calcification are the largest patient group benefiting from TE grafts. Decellularized AV (DAV; n = 4) and DAV additionally re-endothelialized with autologous cells (n = 3) were implanted in the AV position of 6-year-old female sheep. Function was investigated at implantation and explantation 12 months later. Regeneration capacity was analyzed by the repopulation degree of the graft with recipient's cells, by the generation of a new endothelial layer and by intracellular staining against pro-collagen type I. DAV and re-endothelialized AV demonstrated excellent function with only two valves developing mild insufficiencies (1°). Of the repopulating cells only few cells were identified as inflammation cells, while the majority was found to be interstitial cells producing procollagen type I. Endothelial coverage was found, but seemed to be reduced. The regenerative capacity of decellularized matrix is not only a feature exhibited when implanted in juvenile individuals but also is evident when implanted in the high-pressure AV position of older sheep, revealing the potential of TE grafts in age-advanced patients.

Recellularized bovine pericardium with autologous mesenchymal stem cells reduces immune activation

“…To date, an incredible amount of work has been done in conceptualizing and creating tissue engineered heart valves(TEHVs) 37 . TEHVs are made with a variety of techniques, including decellularized xenografts, decellularized allografts, synthetic recellularized scaffolds, and xenogenic recellularized scaffolds 23,25,38–43 . Recellularization of these scaffolds has been hypothesized to provide an immunoprivileged tissue; one that does not generate an immune response.…”

“…37 TEHVs are made with a variety of techniques, including decellularized xenografts, decellularized allografts, synthetic recellularized scaffolds, and xenogenic recellularized scaffolds. 23,25,[38][39][40][41][42][43] Recellularization of these scaffolds has been hypothesized to provide an immunoprivileged tissue; one that does not generate an immune response. The current study provides evidence that autologous MSC recellularization attenuates the acute immune response, without adversely affecting the ECM scaffold's biochemical composition.…”

Models and Techniques to Study Aortic Valve Calcification in Vitro, ex Vivo and in Vivo. An Overview

“…For example, naturally occurring and experimental aortic stenosis has been investigated in dogs ( Copeland et al, 1974 ; Kim et al, 1986 ; Ahlstrom Ast et al, 2008 ). Sheep are routinely used as a big animal model to investigate calcification of biological aortic valve prosthesis and homografts in vivo ( Kheradvar et al, 2017 ; Theodoridis et al, 2017 ; Bester et al, 2018 ). Apparently, calcification occurs very rapidly in sheep compared to humans.…”

Strategies to Improve Survival from Surgery for Heart Valve Implantation in Sheep

“…19 Consequently, high on-table mortality rates, ranging from 9% to 33%, have been reported. 1,18,21,24 Furthermore, the incidence of mortality during the first 30 d after surgery, directly related to the surgical procedure, is often high, ranging from 17% to 50%. 1,2,16,18,21 Therefore, optimizing cardioprotective strategies during surgery would improve postoperative survival.…”