Implantation of a Tissue-engineered Heart Valve from Human Fibroblasts Exhibiting Short Term Function in the Sheep Pulmonary Artery

Abstract

Abstract-We have previously demonstrated the feasibility of fabricating a fibrin-based tissue-engineered heart valve (TEHV) using neonatal human dermal fibroblasts (nhDF), including leaflets with structural and mechanical anisotropy similar to native leaflets. The aim here was to evaluate the performance of this TEHV in a pilot study using the sheep model. Bi-leaflet TEHV were conditioned in a cyclic stretching bioreactor, then implanted within a polymeric sleeve interpositionally into the pulmonary artery of four sheep, with the pulmonary valve either left intact or rendered incompetent. Heparin and immunosuppression were administered for the duration. Echocardiography was performed at implantation and at 4 and 8 weeks. Explants were examined histologically, biochemically, and mechanically. In all sheep, echocardiography at implantation showed coapting leaflets, with minimal valve regurgitation and no turbulence. Orifice area and pressure gradients at systole approached the native pulmonary valve values. Echocardiography at 4 weeks revealed both leaflets functional with moderate regurgitation and turbulence in three sheep; in one sheep, only one leaflet was evident. Explanted leaflets had thickness and tensile properties comparable to the implanted leaflets. There was extensive endothelialization of the root lumenal surface. In the two sheep continued to 8 weeks, only one shortened leaflet remained in both cases. Immunocytochemistry indicated this was due to sustained tissue contraction caused by the nhDF and not by the invading host cells, which included a subpopulation consistent with bone marrow-derived cells. Short-term success was thus achieved in terms of excellent valve function at implantation and some valve function for at least 4 weeks; however, an apparent progressive tissue contraction needs to be resolved for long-term success.

Adipose Derived Tissue Engineered Heart Valve

“…This phenomenon, which was also observed in TEHV based on other cell types [52,53], might be the result of the complete relaxation of the stent after harvest or of the relatively high amount of α-SMA. Elimination of cellular components (decellularization) of the TEHV might strongly reduce this problem, without altering the collagen structure or tissue strength [47].…”

Passive and active contributions to generated force and retraction in heart valve tissue engineering

“…Recovery from CytoD and ROCK at 20% FBS occurred within 8 h and in vivo this will likely be faster due to higher serum concentrations. A recent study of Seydain et al confirms these expectations (Syedain et al 2011). They treated fibrinbased tissue engineered heart valves with blebbistatin before implantation to decrease retraction.…”

“…However, there are still some challenges that need to be overcome. One of those challenges is cell-mediated leaflet retraction, causing regurgitation in vivo (Flanagan et al 2009;Gottlieb et al 2010;Syedain et al 2011). In general, this regurgitation has been neglected and reported to be only mild.…”

Tissue-Engineered Fibrin-Based Heart Valve with a Tubular Leaflet Design

“…Animal studies on fibrin-based tissue-engineered heart valves 29,41 revealed an absence of thrombus formation, calcification, stenosis, or aneurysm development. This together with the excellent tissue remodelling shows the potential of TEHVs based on an autologous fibrin scaffold.…”

“…A confluent monolayer of endothelial cells was found on the whole valve surface 3 months after implantation 29 and extensive endothelialization was observed on the root lumen but not on the leaflet 8 weeks after implantation. 41 Flanagan and colleagues, differently from Syedain and coworkers, performed a short endothelialization process in vitro (30 min), but no efficiency of the process was reported. While it can be argued that sheep are able to endothelialize a variety of prostheses that are implanted in the circulation, 42 pericardial tissue valves were only partially covered with endothelial cells after 11 months in vivo in the sheep model.…”