Development of a Novel Human Cell-Derived Tissue-Engineered Heart Valve for Transcatheter Aortic Valve Replacement: an In Vitro and In Vivo Feasibility Study

Abstract

Transcatheter aortic valve replacement (TAVR) is being extended to younger patients. However, TAVR-compatible bioprostheses are based on xenogeneic materials with limited durability. Off-the-shelf tissue-engineered heart valves (TEHVs) with remodeling capacity may overcome the shortcomings of current TAVR devices. Here, we develop for the first time a TEHV for TAVR, based on human cell-derived extracellular matrix and integrated into a state-of-the-art stent for TAVR. The TEHVs, characterized by a dense acellular collagenous matrix, demonstrated in vitro functionality under aortic pressure conditions (n = 4). Next, transapical TAVR feasibility and in vivo TEHV functionality were assessed in acute studies (n = 5) in sheep. The valves successfully coped with the aortic environment, showing normal leaflet motion, free coronary flow, and absence of stenosis or paravalvular leak. At explantation, TEHVs presented full structural integrity and initial cell infiltration. Its long-term performance proven, such TEHV could fulfill the need for next-generation lifelong TAVR prostheses.

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 – 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 trans-anastomotic outgrowth seen in sheep.…”

“…Using the senescent baboon model ( 335 ) and the sheep model—first for transcatheter pulmonary valve replacements ( 336 – 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 trans-anastomotic outgrowth seen in sheep. Furthermore, leaflet shrinkage as a consequence of repopulation emerged as an inevitable consequence of early tissue maturation ( 335 , 336 , 338 ) but could be addressed by shape compensation during production ( 340 ).…”

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

“…16–26 Decellularized TEM showed efficient cell depletion as well as matrix preservation in a comparative in vitro study, 16 as well as in several in vivo studies. 16–18,21,22 Here, decellularized TEM-based TEHVs demonstrated superior long-term functionality and comparable mechanical properties to cellularized in vitro grown TEHVs. In support of this, numerous preclinical studies have proven the regenerative properties of decellularized TEM-based TEHVs, also when implanted with transcatheter techniques in large preclinical animal models.…”

“…18,28,30 By using an insert to implement such design, 18,28,29 the TEM-based TEHVs have been implanted in the sheep model, 18 demonstrating excellent long-term functionality and reduction of the maladaptive remodeling phenomena observed in the previous generations of TEHVs (i.e., leaflet retraction and valve insufficiency). 9,17,21,22 These results suggest the importance of mimicking the physiological valve design to ensure long-term performance of the prosthesis.…”

Preclinical Assessment of Cardiac Valve Substitutes: Current Status and Considerations for Engineered Tissue Heart Valves

“…Thus, although calcification is frequently encountered in experimental heart valves composed of tissue or polymer, especially in the widely-used sheep models, it is uncertain whether this process will be limiting in humans implanted with engineered tissue heart valves. (12, 51, 52).…”