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Bone Marrow Mononuclear Cell Preseeding on Bioresorbable Elastomeric Tissue Engineered Heart Valves for Transcatheter Pulmonary Valve Replacement: a Word of Caution.
Emanuela S. Fioretta1, Valentina Lintas1, Matilde Putti2, Sarah E. Motta1, Anthal I. Smits2, Petra E. Dijkman1, Nikola Cesarovic3, Etem Caliskan3, Hector Rodriguez3, Henk M. Janssen4, Serge H. Söntjens4, Carlijn V. Bouten2, Maximilian Y. Emmert1, Simon P. Hoerstrup1.
1University of Zurich, Zurich, Switzerland, 2Eindhoven University of Technology, Eindhoven, Netherlands, 3University Hospital Zurich, Zurich, Switzerland, 4SyMO-Chem B.V., Eindhoven, Netherlands.

OBJECTIVE: Initially developed for inoperable cases, transcatheter valve replacement (TVR) is being extended to lower-risk and younger patients. Tissue engineering aims at solving the degenerative complications of current bioprostheses compatible with TVR by providing a replacement that transforms into a living valve upon implantation.
METHODS: We used cell-free bioresorbable elastomeric tissue engineered heart valves (TEHVs) for transcatheter pulmonary valve replacement in a preclinical sheep model. To favour in-vivo remodelling via paracrine signalling, we developed a one-step procedure prior implantation to test the role of autologous bone marrow mononuclear cells (BMMNCs) pre-seeding on the TEHVs. For each group (cell-free, pre-seeded), 4 (n=2) and 24 (n=3) weeks follow-up in sheep were performed (total n=10).
RESULTS: Cell-free TEHVs showed stable functionality and good remodelling potential for up to 24 weeks, demonstrating integration into the native tissues, cellular infiltration, collagen and elastin deposition, and initial scaffold degradation. Despite its feasibility, the BMMNCs pre-seeding had detrimental effects on valve functionality and tissue remodelling. Upon implantation and up to 4 weeks, the BMMNC-seeded valves showed sufficient functionality, but fusion of contiguous leaflets was already evident in the 4 weeks explants (n=2). Starting at 12 weeks, moderate regurgitation was observed, and worsened over time leading to pre-term sacrifice at 18 weeks (n=2). Histological evaluation revealed abundant presence of αSMA-positive cells, calcified nodules, and signs of leaflet thickening and retraction. Independently on the pre-seeding, leaflet-specific remodelling, in terms of thickening, cellular infiltration, and elastin deposition, was evident for all the TEHVs.
CONCLUSIONS: Taken together, these results suggest that, albeit feasible, BMMNC-seeding is associated with maladaptive valve remodelling. Further studies should investigate the causes for the observed leaflet-dependent remodelling mechanisms to increase the safety profile of the valve, before achieving a competitive and clinically relevant valve replacement solution.


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