Human cell-derived tissue-engineered heart valve with integrated Valsalva sinuses: towards native-like transcatheter pulmonary valve replacements

Abstract

Transcatheter valve replacement indication is currently being extended to younger and lower-risk patients. However, transcatheter prostheses are still based on glutaraldehyde-fixed xenogeneic materials. Hence, they are prone to calcification and long-term structural degeneration, which are particularly accelerated in younger patients. Tissue-engineered heart valves based on decellularized in vitro grown tissue-engineered matrices (TEM) have been suggested as a valid alternative to currently used bioprostheses, showing good performance and remodeling capacity as transcatheter pulmonary valve replacement (TPVR) in sheep. Here, we first describe the in vitro development of human cell-derived TEM (hTEM) and their application as tissue-engineered sinus valves (hTESVs), endowed with Valsalva sinuses for TPVR. The hTEM and hTESVs were systematically characterized in vitro by histology, immunofluorescence, and biochemical analyses, before they were evaluated in a pulse duplicator system under physiological pulmonary pressure conditions. Thereafter, transapical delivery of hTESVs was tested for feasibility and safety in a translational sheep model, achieving good valve performance and early cellular infiltration. This study demonstrates the principal feasibility of clinically relevant hTEM to manufacture hTESVs for TPVR.

Progressive Reinvention or Destination Lost? Half a Century of Cardiovascular Tissue Engineering

“…The group in Zurich decellularized their well-established tissue engineered constructs of cultured human fibroblasts on a degradable scaffold (335). Using the senescent baboon model (335) and the sheep model-first for transcatheter pulmonary valve replacements (336)(337)(338) and later for orthotopic TAVIs (339)-in depth repopulation of such a matrix with mesenchymal cells was demonstrated. The patchy endothelial cover of the leaflets (158, 339), however, again hinted at the likely dependence of surface repopulation on the transanastomotic outgrowth seen in sheep.…”

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

“…The approach of in situ tissue-engineered heart valves (TEHVs) relies on endogenous colonization of the implanted valve prosthesis by host cells, followed by tissue formation and remodeling, whereas the implanted valvular scaffold is gradually resorbed ( 8 , 9 ). Although there are some data on the in situ tissue engineering of heart valves using natural materials, such as decellularized allografts, xenografts ( 10 , 11 , 12 ), or decellularized de novo engineered matrixes ( 13 , 14 , 15 , 16 , 17 , 18 ), the availability of long-term in vivo data on resorbable synthetic heart valves is currently limited [for a detailed overview on TEHVs, please see Mela et al. ( 19 )].…”

Engineering Cell‐Derived Matrices: From 3D Models to Advanced Personalized Therapies

“…CDMs have also been applied to produce human tissue‐engineered sinus cardiac valves. [ 189 ] Clinically relevant off‐the‐shelf valves were produced using human neonatal dermal fibroblasts (hDF), with different concentrations of TGF‐β1 used to induce matrix production. After decellularization, in vivo evaluation was performed in a translational sheep model.…”