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Inflammatory And Regenerative Processes In Bioresorbable Synthetic Pulmonary Valves Up To Two Years In Sheep: The Role Of Hemodynamics
Bente de Kort1, Julia Marzi2, Eva Brauchle2, Arturo Lichauco1, Hannah Bauer3, Aurelie Serrero3, Sylvia Dekker1, Martijn Cox3, Katja Schenke-Layland2, Fred Schoen4, Carlijn Bouten1, Anthal Smits1.
1Tue, Eindhoven, Netherlands, 2Eberhard Karls university, Tübingen, Germany, 3Xeltis BV, Eindhoven, Netherlands, 4Harvard medical school, Boston, MA, USA.

OBJECTIVE: In situ tissue engineering (TE) is a promising approach to create optimized heart valve replacements capable of growth and remodeling, as shown in multiple pre-clinical and clinical trials. However, substantial valve-to-valve variability and unexpected and uncontrolled (mal)adaptive remodeling is also reported. To ensure safe clinical translation, further in-depth understanding of the processes essential in in situ heart valve regeneration is necessary.
METHODS: Explanted ovine pulmonary XPV valved conduits with an extensive follow up time up to two years were analyzed on both molecular and protein level by combining Raman microspectroscopy and immunohistochemistry, respectively, spatiotemporally mapping cellular infiltration, inflammation, graft resorption, and tissue remodeling. Based on these findings, further hypothesis-driven in vitro research on the effect of hemodynamics on these processes was performed.
RESULTS: Graft resorption was strongly location-dependent with most pronounced resorption at the conduit and leaflet base region, which correlated with the presence of foreign body giant cells. Moreover, valve-to-valve variability in the spatiotemporal distribution of (immune) cells, endogenous tissue, and graft resorption was detected. Differences in the local stretch were assumed to be a predominant cause of this variability. In order to mechanistically investigate this, systematic in vitro studies on the effect of cyclic stretch on immune cell activation and function in 3D scaffolds are being performed.
CONCLUSIONS: Based on the combined findings of in vivo and in vitro experiments, we conclude that hemodynamic loading, and specifically cyclic stretch, plays an important role in the local inflammatory response to a valvular scaffold, causing spatiotemporal variability in tissue formation and scaffold resorption. These findings contribute to the mechanistic understanding of in situ tissue regeneration, which is essential to achieve predictive applicability, especially when progressing from pulmonary to aortic heart valve replacements.


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