Biomimetic biaxial mechanical properties enhance hemodynamic performance and prevent adverse tissue remodelling in tissue-engineered heart valves

Heart valve tissue engineering holds the promise of providing an unlimited supply of heart valve replacements for patients with valvular heart disease. While tissue-engineered heart valves show promising performance in the short term, regurgitation due to fibrotic leaflet shortening remains a persistent limitation in most cases. Here we tested the hypothesis that engineering heart valves with native biaxial mechanical properties would mitigate adverse tissue remodeling in vitro. Melt electrowriting and hydrogel casting were used to generate four types of tissue-engineered heart valves with combinatorial biomimetic or non-biomimetic mechanical properties in the radial and circumferential direction of the heart valves. The heart valves were subject to pulmonary hemodynamic conditions in a pulse duplicator bioreactor, and their tissue remodelling, including cell phenotype and orientation and extracellular matrix properties, was investigated. The results showed that tissue-engineered heart valves with native mechanical properties, particularly in the radial direction, outperformed those with non-physiological mechanics in hemodynamic function, maintaining quiescent cell phenotype and cell orientation, and avoiding fibrosis. This study, for the first time, elucidates the impact of native mechanical properties on the performance of tissue- engineered heart valves and their cell and extracellular matrix homeostasis.