Abstract Objectives(s) Cardiac allometric organ growth following pediatric valve replacement can lead to patient-prosthesis size mismatch and valve re-replacement, which could be mitigated with ...allogeneic decellularized pulmonary valves treated with collagen conditioning solutions to enhance biological and mechanical performance termed “bioengineered valves”. This study tested functional, dimensional, and biological responses of these bioengineered valves versus traditional cryopreserved valves implanted in lambs during rapid somatic growth. Methods From a consanguineous flock of 13, the pulmonary valves of ten lambs (19.6±1.4 kg) were replaced with 7 bioengineered valves or 3 classically cryopreserved valves. After 6 months, implanted valves and 3 untreated flock-mates were compared by echocardiography, cardiac catheterization and explant pathology. Results Increases in body mass, valve geometric dimensions, and effective orifice areas were similar. Bioengineered valve had higher cusp-to-cusp coaptation areas (34.6(39.8)%) and were more similar to native (43.4(2.83)%median (range)) than were cryopreserved valves (13.2(13.7)%) (P=0.043). Cryopreserved but not bioengineered cusps were thicker than native (P=0.01). Histologically, cryopreserved demonstrated less than native cellularity while bioengineered valves that were acellular at the time of surgery gained surface endothelium and subsurface myofibroblast interstitial cells in pulmonary artery, sinus wall and cusp base regions. Conclusions Biological valved conduits can enlarge via passive dilatation without matrix synthesis, but this would result in decreased cusp coaptational areas. Bioengineered valves demonstrated equivalent annulus enlargements as cryopreserved valves but usually retained larger areas of cuspal coaptation. Heat-shock protein-47+ (collagen synthesizing) cells were present in previously acellular bioengineered sinus walls and cusp bases, but rarely in more distal cusp matrix.
Objective This study assesses in a baboon model the hemodynamics and human leukocyte antigen immunogenicity of chronically implanted bioengineered (decellularized with collagen conditioning ...treatments) human and baboon heart valve scaffolds. Methods Fourteen baboons underwent pulmonary valve replacement, 8 with decellularized and conditioned (bioengineered) pulmonary valves derived from allogeneic (N = 3) or xenogeneic (human) (N = 5) hearts; for comparison, 6 baboons received clinically relevant reference cryopreserved or porcine valved conduits. Panel-reactive serum antibodies (human leukocyte antigen class I and II), complement fixing antibodies (C1q binding), and C-reactive protein titers were measured serially until elective sacrifice at 10 or 26 weeks. Serial transesophageal echocardiograms measured valve function and geometry. Differences were analyzed with Kruskal–Wallis and Wilcoxon rank-sum tests. Results All animals survived and thrived, exhibiting excellent immediate implanted valve function by transesophageal echocardiograms. Over time, reference valves developed a smaller effective orifice area index (median, 0.84 cm2 /m2 ; range, 1.22 cm2 /m2 ), whereas all bioengineered valves remained normal (effective orifice area index median, 2.45 cm2 /m2 ; range, 1.35 cm2 /m2 ; P = .005). None of the bioengineered valves developed elevated peak transvalvular gradients: 5.5 (6.0) mm Hg versus 12.5 (23.0) mm Hg ( P = .003). Cryopreserved valves provoked the most intense antibody responses. Two of 5 human bioengineered and 2 of 3 baboon bioengineered valves did not provoke any class I antibodies. Bioengineered human (but not baboon) scaffolds provoked class II antibodies. C1q+ antibodies developed in 4 recipients. Conclusions Valve dysfunction correlated with markers for more intense inflammatory provocation. The tested bioengineering methods reduced antigenicity of both human and baboon valves. Bioengineered replacement valves from both species were hemodynamically equivalent to native valves.
Because of cryopreserved heart valve-mediated immune responses, decellularized allograft valves are an attractive option in children and young adults. The objective of this study was to investigate ...the performance and morphologic features of decellularized pulmonary valves implanted in the right ventricular outflow tract of juvenile sheep.
Right ventricular outflow tract reconstructions in juvenile sheep (160±9 days) using cryopreserved pulmonary allografts (n=6), porcine aortic root bioprostheses (n=4), or detergent/enzyme-decellularized pulmonary allografts (n=8) were performed. Valve performance (echocardiography) and morphologic features (gross, radiographic, and histologic examination) were evaluated 20 weeks after implantation.
Decellularization reduced DNA in valve cusps by 99.3%. Bioprosthetic valves had the largest peak and mean gradients versus decellularized valves (p=0.03; p<0.001) and cryopreserved valves (p=0.01; p=0.001), which were similar (p=0.45; p=0.40). Regurgitation was minimal and similar for all groups (p=0.16). No cusp calcification was observed in any valve type. Arterial wall calcification was present in cryopreserved and bioprosthetic grafts but not in decellularized valves. No autologous recellularization or inflammation occurred in bioprostheses, whereas cellularity progressively decreased in cryopreserved grafts. Autologous recellularization was present in decellularized arterial walls and variably extending into the cusps.
Cryopreserved and decellularized graft hemodynamic performance was comparable. Autologous recellularization of the decellularized pulmonary arterial wall was consistently observed, with variable cusp recellularization. As demonstrated in this study, decellularized allograft valves have the potential for autologous recellularization.
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