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PRE-CLINICAL RESEARCH

Minimally-Invasive Implantation of Living Tissue Engineered Heart Valves

A Comprehensive Approach From Autologous Vascular Cells to Stem Cells

Dörthe Schmidt, MD, PhD^_*,,, Petra E. Dijkman, MSc, Anita Driessen-Mol, PhD, Rene Stenger, BSc, Christine Mariani, MSc^||, Arja Puolakka, MSc^||, Marja Rissanen, LicTech^||, Thorsten Deichmann, DiplIng^¶, Bernhard Odermatt, MD^#, Benedikt Weber, MD^_*,,, Maximilian Y. Emmert, MD^_*,,, Gregor Zund, MD, Frank P.T. Baaijens, PhD and Simon P. Hoerstrup, MD, PhD^_*,,,_*

^_* Clinic for Cardiovascular Surgery, University Hospital Zurich, Zurich, Switzerland
Swiss Center for Regenerative Medicine, Zurich, Switzerland
Department of Surgical Research, University Zurich, Zurich, Switzerland
Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands
^|| Department of Materials Science, Tampere University of Technology, Tampere, Finland
^¶ Institute for Textile Techniques, RWTH Aachen University, Aachen, Germany
^# Department of Pathology, University Hospital Zurich, Switzerland

Manuscript received June 12, 2009; revised manuscript received April 8, 2010, accepted April 13, 2010.

^_* Reprint requests and correspondence: Dr. Simon P. Hoerstrup, Clinic for Cardiovascular Surgery, Department of Surgical Research, University Hospital Zurich, Raemistrasse 100, Zurich CH 8091, Switzerland (Email: simon_philipp.hoerstrup{at}usz.ch).

Objectives: The aim of this study was to demonstrate the feasibility of combining the novel heart valve replacement technologies of: 1) tissue engineering; and 2) minimally-invasive implantation based on autologous cells and composite self-expandable biodegradable biomaterials.

Background: Minimally-invasive valve replacement procedures are rapidly evolving as alternative treatment option for patients with valvular heart disease. However, currently used valve substitutes are bioprosthetic and as such have limited durability. To overcome this limitation, tissue engineering technologies provide living autologous valve replacements with regeneration and growth potential.

Methods: Trileaflet heart valves fabricated from biodegradable synthetic scaffolds, integrated in self-expanding stents and seeded with autologous vascular or stem cells (bone marrow and peripheral blood), were generated in vitro using dynamic bioreactors. Subsequently, the tissue engineered heart valves (TEHV) were minimally-invasively implanted as pulmonary valve replacements in sheep. In vivo functionality was assessed by echocardiography and angiography up to 8 weeks. The tissue composition of explanted TEHV and corresponding control valves was analyzed.

Results: The transapical implantations were successful in all animals. The TEHV demonstrated in vivo functionality with mobile but thickened leaflets. Histology revealed layered neotissues with endothelialized surfaces. Quantitative extracellular matrix analysis at 8 weeks showed higher values for deoxyribonucleic acid, collagen, and glycosaminoglycans compared to native valves. Mechanical profiles demonstrated sufficient tissue strength, but less pliability independent of the cell source.

Conclusions: This study demonstrates the principal feasibility of merging tissue engineering and minimally-invasive valve replacement technologies. Using adult stem cells is successful, enabling minimally-invasive cell harvest. Thus, this new technology may enable a valid alternative to current bioprosthetic devices.

Key Words: heart valves • minimally invasive • stem cells • cells • tissue engineering

Abbreviations and Acronyms   DNA = deoxyribonucleic acid   eNOS = endothelial nitric oxide synthase   GAG = glycosaminoglycans   OD = outer diameter   SMA = smooth muscle actin   TEHV = tissue engineered heart valve   UTS = ultimate tensile strength

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