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The main treatment for valvular disease consists in surgical replacement with mechanical or biological artificial devices; these are excellent mid-term replacements which greatly improve the patient’s quality of life. However, long-term use of these devices (beyond 10-15 years) is associated with bleeding risks in the case of mechanical valves and degeneration, for biological valves (1). Heart valve tissue engineering, the science of combining scaffolds and cells has the potential to revolutionize the field of valve surgery by providing functional, durable, and viable valves. To date, several approaches have been tested using synthetic and natural scaffolds and a variety of cells and bioreactors, but overall most approaches have not been successful on the long term when tested in animals or human patients as pulmonary or aortic implants (1-4). We hypothesized that one potential approach would be based on well characterized xenogeneic acellular aortic valve root scaffolds seeded with autologous adipose-tissue derived stem cells (ASCs). To test this hypothesis, we prepared porcine acellular aortic roots, injected them with autologous ASCs and implanted them in the right ventricular outflow tract (RVOT) of juvenile sheep. Porcine valve roots were decellularized with detergents and enzymes using a pressurized perfusion system and then stabilized with polyphenols as described before (5). Male juvenile sheep weighing about 35 kg were used for this study. After acclimation, we collected inter-scapular adipose tissue from each animal, isolated ASCs using a published collagenase-based procedure (6) and propagated them in culture for 3-4 passages. We then mounted each acellular aortic root within a decellularized bovine pericardial tube and seeded each cusp with 4 million autologous ASCs in 200 ul PBS by injection into the base of each cusp. ASC-seeded valved conduits were then implanted under general anesthesia in the right ventricle outflow tract (RVOT) with full ligation of the native pulmonary artery. Six animals (n=6) underwent implantation with autologous ASC-seeded valves and one with a non-cell seeded valve as control. Postoperatively antalgics, antibiotics, and diuretics were administered for 5 days. Anticoagulant (Fraxiparine 2 x 0.3 ml) therapy was maintained for the first 30 days and anti-aggregant treatment (Aspenter 75 mg/day orally) for the entire length of the study with a target follow-up of 4 months. Monthly transthoracic echography was performed under mild sedation, monitoring the valve hemodynamics, leaflet mobility and thickness and evidence for right ventricular remodeling. All animal procedures were performed in accordance to the “Guide for the care and use of laboratory animals”, published by the NIH (NIH Publication No. 85-23, revised 1996) under an animal use protocol approved by the University of Medicine and Pharmacy Targu Mures Ethical Committee (AUP #8/04.02.2012).

In Vivo Testing of Xenogeneic Acellular Aortic Valves Seeded with Stem Cells