Agnieszka A Książek1,2,3,4, Katharyn J Mitchell5, Nikola Cesarovic2, Colin C Schwarzwald4,5,6, Simon P Hoerstrup1,2,3,4,6, Benedikt Weber1,2,3,4,6,7. 1. Institute for Regenerative Medicine, University of Zurich, Switzerland. 2. Division of Surgical Research, University and University Hospital of Zurich, Switzerland. 3. Clinic for Cardiovascular Surgery, University Hospital Zurich, Zurich, Switzerland. 4. Competence Center for Applied Biotechnology and Molecular Medicine (CABMM), Vetsuisse Faculty, University of Zurich, Zurich, Switzerland. 5. Clinic for Equine Internal Medicine, Equine Hospital, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland. 6. Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland. 7. Department of Dermatology and Venerology, Vascular Research Group, University Hospital Zurich, Zurich, Switzerland. Electronic correspondence: benedikt.weber@usz.ch.
Abstract
BACKGROUND AND AIM OF THE STUDY: Bioengineered living autologous valves with remodeling and growth capacity represent a promising concept for future cardiac and venous valve repair. A meticulous understanding of the mechanisms involved in recellularization and remodeling is essential for the safe and efficient clinical translation of this technology. In this context, the first investigations of bioengineered vascular grafts in immune-incompetent or transgenic rodents represented an important step. However, the in-vivo assessment of bioengineered synthetic scaffold-based (biodegradable) valve replacements in rodent models has not been achieved to date. METHODS: Miniaturized monocuspid PGA (polyglycolic acid)-P4HB (poly-4-hydroxybutyrate)-based valves were created, incorporated into metallic stents (length 2.0 mm, diameter 1.1 mm) and introduced into catheter-based implantation devices. Wistar outbred rats (n = 8) underwent a laparotomy, abdominal aorta arteriotomy and valve delivery into the abdominal aorta. Valve placement and function were evaluated following deployment using ultrasound (Doppler- and M-mode). Explanted tissues were analyzed both macroscopically and histopathologically. RESULTS: No significant physiological or hemodynamic changes were observed, including heart rate, pressure gradients, velocity values and cardiac output before and after valve implantation. The cross-sectional area at the level of the stented valve was reduced by 22%. Valvular leaflet oscillation was observed in two animals, and thrombus formation in the stent was observed in one animal. Histological evaluation revealed cellular infiltration within 3 h in vivo, and no signs of thrombus deposition on the valvular surface. CONCLUSIONS: This study demonstrated the technical feasibility of the transcatheter implantation of bioengineered stented miniaturized valves into the infrarenal rat aorta, without affecting the animal's physiological and hemodynamic variables and with valvular oscillation in part of the implants. These results could serve as a basis for the implementation of a chronic rat in-vivo model for mechanistic studies in bioengineered valvular tissues under systemic hemodynamic conditions. Video 1: 2D ultrasonographic projection revealing graft's leaflet oscillation.
BACKGROUND AND AIM OF THE STUDY: Bioengineered living autologous valves with remodeling and growth capacity represent a promising concept for future cardiac and venous valve repair. A meticulous understanding of the mechanisms involved in recellularization and remodeling is essential for the safe and efficient clinical translation of this technology. In this context, the first investigations of bioengineered vascular grafts in immune-incompetent or transgenic rodents represented an important step. However, the in-vivo assessment of bioengineered synthetic scaffold-based (biodegradable) valve replacements in rodent models has not been achieved to date. METHODS: Miniaturized monocuspid PGA (polyglycolic acid)-P4HB (poly-4-hydroxybutyrate)-based valves were created, incorporated into metallic stents (length 2.0 mm, diameter 1.1 mm) and introduced into catheter-based implantation devices. Wistar outbred rats (n = 8) underwent a laparotomy, abdominal aorta arteriotomy and valve delivery into the abdominal aorta. Valve placement and function were evaluated following deployment using ultrasound (Doppler- and M-mode). Explanted tissues were analyzed both macroscopically and histopathologically. RESULTS: No significant physiological or hemodynamic changes were observed, including heart rate, pressure gradients, velocity values and cardiac output before and after valve implantation. The cross-sectional area at the level of the stented valve was reduced by 22%. Valvular leaflet oscillation was observed in two animals, and thrombus formation in the stent was observed in one animal. Histological evaluation revealed cellular infiltration within 3 h in vivo, and no signs of thrombus deposition on the valvular surface. CONCLUSIONS: This study demonstrated the technical feasibility of the transcatheter implantation of bioengineered stented miniaturized valves into the infrarenal rat aorta, without affecting the animal's physiological and hemodynamic variables and with valvular oscillation in part of the implants. These results could serve as a basis for the implementation of a chronic rat in-vivo model for mechanistic studies in bioengineered valvular tissues under systemic hemodynamic conditions. Video 1: 2D ultrasonographic projection revealing graft's leaflet oscillation.