In Situ Remodeling Overrules Bioinspired Scaffold Architecture of Supramolecular Elastomeric Tissue-Engineered Heart Valves.

In situ tissue engineering that uses resorbable synthetic heart valve scaffolds is an affordable and practical approach for heart valve replacement; therefore, it is attractive for clinical use. This study showed no consistent collagen organization in the predefined direction of electrospun scaffolds made from a resorbable supramolecular elastomer with random or circumferentially aligned fibers, after 12 months of implantation in sheep. These unexpected findings and the observed intervalvular variability highlight the need for a mechanistic understanding of the long-term in situ remodeling processes in large animal models to improve predictability of outcome toward robust and safe clinical application.

In situ heart valve tissue engineering using a bioresorbable elastomeric implant - From material design to 12 months follow-up in sheep.

The creation of a living heart valve is a much-wanted alternative for current valve prostheses that suffer from limited durability and thromboembolic complications. Current strategies to create such valves, however, require the use of cells for in vitro culture, or decellularized human- or animal-derived donor tissue for in situ engineering. Here, we propose and demonstrate proof-of-concept of in situ heart valve tissue engineering using a synthetic approach, in which a cell-free, slow degrading elastomeric valvular implant is populated by endogenous cells to form new valvular tissue inside the heart. We designed a fibrous valvular scaffold, fabricated from a novel supramolecular elastomer, that enables endogenous cells to enter and produce matrix. Orthotopic implantations as pulmonary valve in sheep demonstrated sustained functionality up to 12 months, while the implant was gradually replaced by a layered collagen and elastic matrix in pace with cell-driven polymer resorption. Our results offer new perspectives for endogenous heart valve replacement starting from a readily-available synthetic graft that is compatible with surgical and transcatheter implantation procedures.

Degree of scaffold degradation influences collagen (re)orientation in engineered tissues.

Tissue engineering provides a promising tool for creating load-bearing cardiovascular tissues. Ideally, the neotissue produced by cells possesses native strength and anisotropy. By providing contact-guiding cues with microfibers, scaffold directionality can guide tissue organization. However, scaffolds transiently degrade, which may induce undesired tissue remodeling in response to applied strain. We hypothesize that in newly formed tissues, the collagen matrix does not yet provide contact guidance to the cells, and collagen orientation is altered via strain-induced remodeling. To test this hypothesis, we studied the influence of lipase-induced scaffold degradation on collagen (re)orientation at static constraint. Myofibroblasts were cultured in electrospun PCL-U4U anisotropic microfiber scaffolds, which were statically constrained perpendicular to the scaffold fibers. During 2 weeks of culture, neotissue formation aligned in the direction of the scaffold fibers, after which scaffolds were degraded to different degrees (12%, 27%, and 79% reduction in scaffold weight) and collagen (re)orientation was studied after one additional week of culturing. High degrees of scaffold degradation (79%) were associated with remodeling of the collagen toward the constraint direction, while collagen organization was maintained at low degrees of scaffold degradation. These results highlight the importance of slow scaffold degradation when aiming at maintaining collagen orientation.