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In Vivo Structure and Function of Engineered Pulmonary Valves
Danielle Gottlieb1, Kunal Tandon1, Sitaram Emani1, Elena Aikawa2, David W. Brown1, Andrew J. Powell1, Arthur Nedder1, Michael S. Sacks3, John E. Mayer1; 1Children's Hospital Boston and Harvard Medical School, Boston, MA; 2Massachusetts General Hospital and Harvard Medical School, Boston, MA; 3University of Pittsburgh, Pittsburgh, PA
READER COMMENTS
Objective: Clinical translation of engineered heart valves requires valve competency in the short and long-term. Early studies of engineered heart valves showed promise, though lacked complete definition of valve function. Building on prior experiments, we sought to define a time course of the in vivo changes in structure and function of autologous engineered pulmonary valves (PV).
Methods: Mesenchymal stem cells (MSCs) were isolated from the mononuclear fraction of bone marrow collected from nine neonatal lambs. Cells were characterized, expanded, and seeded onto a 3D heart valve scaffold composed of polyglycolic acid (PGA) and poly-L-lactic acid (PLLA). After 4 weeks of culture, sheep underwent autologous PV replacement on cardiopulmonary bypass. Valve function was evaluated by epicardial echocardiography at implantation, by MRI at the experimental midpoint, and by epicardial echocardiography at explant of the valve at either 6 weeks (n=3), 12 weeks (n=3), or 20 weeks (n=3) post-operatively. Conduit size was measured at the time of implantation and at explantation. Explanted tissues were processed for histology.
Results: All nine animals survived and were clinically well until valve explant. Evaluation of immediate valve function demonstrated a mean transvalvar gradient of 15.2mmHg (range 10-20mmHg), and mean pulmonary regurgitation (PR) score of 0.58 (trivial=0, mild=1, moderate=2, severe=3). Valve function remained adequate at 3 and 6 weeks (PR fraction ≤ 20%), though leaflets appeared increasingly immobile, resulting in an increasing regurgitant fraction over time. Conduit diameter was unchanged over 20 weeks. Engineered leaflets and conduit walls underwent dynamic remodeling over the time course, as evidenced by cell proliferation (Ki67), inflammation (CD45), remodeling enzyme expression (MMP-1, -2, -9, -13) and microvessel formation (CD31) at the early stages, and progressive GAG (versican) and collagen organization (anti-collagen; Masson trichrome) and complete endothelization in long-term explants.
Conclusion: In the largest in vivo series published, we demonstrate reproducible fabrication and implantation of autologous engineered pulmonary valves which function well at implantation. In vivo valves undergo structural and functional remodeling resulting in the onset of pulmonary regurgitation after 6 post-operative weeks. Tissue engineered conduits stayed stable in size after 5 months with no evidence of conduit stenosis or aneurysm formation.


Figure. Representative short axis epicardial echocardiographic view of an engineered pulmonary valved conduit at the time of implantation.
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