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(Circulation. 2002;106:I-143.)
© 2002 American Heart Association, Inc.

Thoracic Transplantation and Mechanical Support for Congestive Heart Failure

Tissue Engineering of Functional Trileaflet Heart Valves From Human Marrow Stromal Cells

Simon P. Hoerstrup, MD; Alexander Kadner, MD; Serguei Melnitchouk, MD; Andreas Trojan, MD; Karim Eid, MD; Jay Tracy; Ralf Sodian, MD; Jeroen F. Visjager, PhD; Stefan A. Kolb, MD; Jurg Grunenfelder, MD; Gregor Zund, MD; Marko I. Turina, MD

From the Departments of Cardiovascular Surgery (S.P.H., A.K., S.M., J.T., J.G., G.Z., M.I.T.), Trauma Surgery (A.T.), Internal Medicine (K.E.), and Pathology (S.A.K.), University Hospital, Zurich, Switzerland; Department of Cardiac Surgery, German Heart Institute, Berlin, Germany (R.S.); Department of Biomechanics, Federal Institute of Technology, Zurich, Switzerland (J.F.V.).

Correspondence to Simon Philipp Hoerstrup, MD, Department of Cardiovascular Surgery, University Hospital Zurich, Raemistrasse 100, CH 8091 Zurich, Switzerland. E-mail simon-philipp.hoerstrup{at}chi.usz.ch

Abstract

Background We previously demonstrated the successful tissue engineering and implantation of functioning autologous heart valves based on vascular-derived cells. Human marrow stromal cells (MSC) exhibit the potential to differentiate into multiple cell-lineages and can be easily obtained clinically. The feasibility of creating tissue engineered heart valves (TEHV) from MSC as an alternative cell source, and the impact of a biomimetic in vitro environment on tissue differentiation was investigated.

Methods and Results Human MSC were isolated, expanded in culture, and characterized by flow-cytometry and immunohistochemistry. Trileaflet heart valves fabricated from rapidly bioabsorbable polymers were seeded with MSC and grown in vitro in a pulsatile-flow-bioreactor. Morphological characterization included histology and electron microscopy (EM). Extracellular matrix (ECM)-formation was analyzed by immunohistochemistry, ECM protein content (collagen, glycosaminoglycan) and cell proliferation (DNA) were biochemically quantified. Biomechanical evaluation was performed using Instron^TM. In all valves synchronous opening and closing was observed in the bioreactor. Flow-cytometry of MSC pre-seeding was positive for ASMA, vimentin, negative for CD 31, LDL, CD 14. Histology of the TEHV-leaflets demonstrated viable tissue and ECM formation. EM demonstrated cell elements typical of viable, secretionally active myofibroblasts (actin/myosin filaments, collagen fibrils, elastin) and confluent, homogenous tissue surfaces. Collagen types I, III, ASMA, and vimentin were detected in the TEHV-leaflets. Mechanical properties of the TEHV-leaflets were comparable to native tissue.

Conclusion Generation of functional TEHV from human MSC was feasible utilizing a biomimetic in vitro environment. The neo-tissue showed morphological features and mechanical properties of human native-heart-valve tissue. The human MSC demonstrated characteristics of myofibroblast differentiation.

Key Words: tissue engineering • valves • cells • prosthesis