Abstract
The cardiovascular system transports oxygen, nutrients and metabolic waste through your body. Specifically, the heart ensures oxygenated blood reaches tissues and deoxygenated blood reaches the lungs. In order to ensure one-way blood flow from the heart to the arteries, there are semilunar pulmonary and aortic valves from the heart to the pulmonary and aortic arteries, respectively. Valvular diseases, affecting about 2.5% of the U.S. population, can be congenital (e.g., bicuspid valves where two leaflets do not separate properly) or caused by degenerative processes (e.g., calcifications). Current treatments include prosthetic valves made from animal tissue (bioprosthetic) or synthetic materials (mechanical), but neither can grow. This is problematic for pediatric patients as it will require staged interventions to accommodate their growth. Tissue-engineered heart valves (TEHVs) offer a potential solution as they regenerate native-like, living, functional valves. Specifically, we focus on an approach where a material without cells is implanted, which attracts the patient’s cells, and these cells remodel the valve to form a living, functional tissue. In this thesis, I focus on TEHVs made in the lab by seeding cells onto a scaffold to produce extracellular matrix (ECM), and then decellularizing the material to reduce immune reactions after implantation. While early results are promising, long-term issues, such as valve malfunction due to tissue retraction, remain. Several studies indicated that leaflet mechanics (for example how the leaflet deforms) are key influencers of how these TEHVs adapt after implantation. On top of that, a recent proof-of-concept study has shown how computational models could be utilized to predict a design that guided mechano-mediated remodeling towards an adaptive state. Subsequent in-vivo studies showed that these valves performed significantly better when implanted as a pulmonary valve, with proper valve functionality for up to a year. However, previous studies have not yet systematically investigated a wide range of designs for high-pressure environments like the aorta. In the current study, we used computational models to investigate how remodeling (the reorganization of tissue components) and the risk of damage were affected by the TEHV design. We found that a design with a curved belly profile and smooth curved attachment edge of the leaflet to the stent promotes long-term functionality and decreases the risk of damage, but design adjustments based on the specific hemodynamic environment (e.g. blood pressure) are necessary to optimize performance. Additionally, we reestablished a dynamic conditioning system to develop the TEHVs in-vitro. We furthermore prototyped a crown-shaped device to guide the attachment edge of TEHV leaflets to the stent. The device is crimpable, biodegradable and off-the-shelf available, and has shown to be compatible with in-vitro production of the TEHVs, making it highly relevant. Finally, we used computational models to explore how cells influence collagen fiber tension during both growth (increase in size) and remodeling (the reorganization of tissue) in different conditions. For example, grafts implanted in locations with lower or higher blood pressure, as is the case in pulmonary or aortic arteries respectively. This model may explain how cells achieve balance in various tissues and help us to design future tissue-engineered implants that keep up with the growth of pediatric patients. We conclude by emphasizing the importance of interdisciplinary research in advancing TEHVs, combining engineering and biomedical science to increase progress and minimize animal testing. Computational models are valuable tools for understanding TEHV integration and guide impactful research in tissue engineering. In the following chapters, I will substantiate why the various methods of interdisciplinary research will rapidly enhance visionary strategies in the field of tissue engineering.
Visser, Valery Lilian