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

Abstract

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.

Computational modeling guides tissue-engineered heart valve design for long-term in vivo performance in a translational sheep model

“…Our results are a step toward the development of a clinically relevant approach. In this context, we also recently reported results using a fully synthetic, cellfree biodegradable polymer as a starter material (10). Although the polymer-based approach is attractive in terms of low costs and manufacturing logistics, it is different from the current study because remodeling is completely based on slowly degrading (>1 year) synthetic materials and therefore is fully dependent on post-implantation tissue formation.…”

“…Although the polymer-based approach is attractive in terms of low costs and manufacturing logistics, it is different from the current study because remodeling is completely based on slowly degrading (>1 year) synthetic materials and therefore is fully dependent on post-implantation tissue formation. Accordingly, long-term safety is still unclear, and further in vivo validation is necessary until the polymer is completely resolved (10). From the clinical translational point of view, TEHVs generated in vitro from competent, homologous neomatrix formed before the time of implantation conceptually provide increased clinical safety profiles.…”

“…In particular, tissue-engineered extracellular matrices (ECMs) depleted of cells have proven to be a valid off-the-shelf alternative to the initially described in vitro TE approaches in several preclinical investigations (11,12,15,18,22). Furthermore, the principal feasibility of implanting biodegradable polymeric scaffolds in a preclinical animal model, which are transformed into cell-repopulated valves in vivo, has been recently demonstrated (10).…”

“…With the introduction of the TE concept more than 20 years ago (8), numerous different heart valve TE approaches have been developed and tested demonstrating principal feasibility in preclinical large-animal models (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). TE concepts were further merged with the latest minimally invasive implantation technologies, and simplifications of the multistep in vitro heart valve TE approaches toward optimized and more clinically relevant "off-the-shelf" strategies were established.…”

Tissue Engineering—Bridging the Gap

“…There is now a move towards an in situ tissue engineering approach where scaffolds are populated by cells after implantation into the patient [12,13]. This approach is feasible with heart valves and vascular tissue [14,15]. Whether such scaffolds are based in synthetic or biological (such as decellularised tissue) materials remains to be determined.…”