Author + information
- Sarah Motta1,
- Emanuela Fioretta2,
- Petra Dijkman2,
- Luc Behr3,
- Simon Hoerstrup4 and
- Maximilian Emmert5
Transcatheter technologies have evolved as a valid option for the treatment of heart valve disease. However, current artificial prostheses are associated to continuous degeneration and thus do not provide a long-term solution for young and children. Hence, tissue-engineered heart valves (TEHVs) with self-repair and regeneration properties may overcome this problem. We recently demonstrated the feasibility of off-the-shelf TEHVs transcatheter delivery in sheep. However, one limitation of these TEHVs was the absence of physiological Valsalva sinuses. Here, we describe the development and in-vivo proof-of-concept of such next-generation regenerative TEHVs using a custom-made sinus stent for transcatheter pulmonary valve replacement.
Ovine cell-derived off-the-shelf TEHVs were manufactured in-vitro, sewn onto a sinus stent and implanted transapically (via thoracotomy) into adult sheep in an acute fashion and for 16 weeks. Valve performance was assessed by angiography and follow-up echocardiography. Additionally, to further fasten clinical translation, a novel scaffold geometry and human fibroblasts were implemented to produce sinus TEHVs and tested in-vitro. Valve remodeling was assessed by histology and immunofluorescence.
Transapical delivery of ovine-derived sinus TEHVs was successful. The valves showed a good acute and short-term performance with proper mobility and coaptation (mild insufficiency) for up to 8 weeks, however it then worsened towards severe regurgitation at 16 weeks. This was most likely due to a non-optimized in-vitro valve design, leading to a non-physiological hemodynamic loading and finally to negative leaflet remodeling. Inspired by these findings the optimized valve geometry was combined with a human cell-source to develop clinically-relevant sinus TEHVs. In-vitro testing of valves showed good performance in a valve pulse duplicator system under physiological pulmonary conditions.
Here we demonstrate the development of a clinically relevant off-the-shelf tissue engineered transcatheter sinus valve. While acute and short-term performance of the acute design is encouraging, further geometry optimization is needed to ensure long-term functionality.
OTHER: Pre-Clinical/First In-Human Studies