Minimally-invasive implantation of living tissue engineered heart valves: a comprehensive approach from autologous vascular cells to stem cells.

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.

[1]  U. Stock,et al.  Prevention of device-related tissue damage during percutaneous deployment of tissue-engineered heart valves. , 2006, The Journal of thoracic and cardiovascular surgery.

[2]  Improved regional wall motion 6 months after direct myocardial revascularization (DMR) with the NOGA DMR system. , 2000, Circulation.

[3]  Takayuki Asahara,et al.  Isolation of Putative Progenitor Endothelial Cells for Angiogenesis , 1997, Science.

[4]  Anita Mol,et al.  Hypoxia Induces Near-Native Mechanical Properties in Engineered Heart Valve Tissue , 2009, Circulation.

[5]  S. Hoerstrup,et al.  Engineering of biologically active living heart valve leaflets using human umbilical cord-derived progenitor cells. , 2006, Tissue engineering.

[6]  Anson Cheung,et al.  Transapical Transcatheter Aortic Valve Implantation in Humans: Initial Clinical Experience , 2006, Circulation.

[7]  Simon P. Hoerstrup,et al.  Tissue Engineering of Functional Trileaflet Heart Valves From Human Marrow Stromal Cells , 2002, Circulation.

[8]  Younes Boudjemline,et al.  Percutaneous insertion of the pulmonary valve. , 2002, Journal of the American College of Cardiology.

[9]  F. Schoen,et al.  Human Semilunar Cardiac Valve Remodeling by Activated Cells From Fetus to Adult: Implications for Postnatal Adaptation, Pathology, and Tissue Engineering , 2006, Circulation.

[10]  Simon P Hoerstrup,et al.  Living Autologous Heart Valves Engineered From Human Prenatally Harvested Progenitors , 2006, Circulation.

[11]  F. Naftolin,et al.  Monitoring of collagen and collagen fragments in chromatography of protein mixtures. , 1980, Analytical biochemistry.

[12]  Philipp Bonhoeffer,et al.  NEW PERCUTANEOUS TREATMENTS FOR VALVE DISEASE , 2007, Heart.

[13]  Mirko Doss,et al.  Transapical Minimally Invasive Aortic Valve Implantation: Multicenter Experience , 2007, Circulation.

[14]  J. Hoffman,et al.  The incidence of congenital heart disease. , 2002, Journal of the American College of Cardiology.

[15]  Michael S Sacks,et al.  From Stem Cells to Viable Autologous Semilunar Heart Valve , 2005, Circulation.

[16]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

[17]  C. Bolognesi,et al.  Improved microfluorometric DNA determination in biological material using 33258 Hoechst. , 1979, Analytical biochemistry.

[18]  Reza Ardehali,et al.  Percutaneous valve replacement: current state and future prospects. , 2004, The Annals of thoracic surgery.

[19]  Marcel C M Rutten,et al.  A physiologically representative in vitro model of the coronary circulation. , 2004, Physiological measurement.

[20]  Assaf Bash,et al.  Early experience with percutaneous transcatheter implantation of heart valve prosthesis for the treatment of end-stage inoperable patients with calcific aortic stenosis. , 2004, Journal of the American College of Cardiology.

[21]  F. Schoen,et al.  Human Pulmonary Valve Progenitor Cells Exhibit Endothelial/Mesenchymal Plasticity in Response to Vascular Endothelial Growth Factor-A and Transforming Growth Factor-&bgr;2 , 2006, Circulation research.

[22]  Frederick J. Schoen,et al.  Early In Vivo Experience With Tissue-Engineered Trileaflet Heart Valves , 2000, Circulation.

[23]  Marcel C. M. Rutten,et al.  Tissue Engineering of Human Heart Valve Leaflets: A Novel Bioreactor for a Strain-Based Conditioning Approach , 2005, Annals of Biomedical Engineering.

[24]  Frank P T Baaijens,et al.  Fibrin as a cell carrier in cardiovascular tissue engineering applications. , 2005, Biomaterials.

[25]  E. Ohman,et al.  Development of systems of care for ST-elevation myocardial infarction patients: evaluation and outcomes. , 2007, Circulation.

[26]  J E Mayer,et al.  New pulsatile bioreactor for in vitro formation of tissue engineered heart valves. , 2000, Tissue engineering.

[27]  S. Hoerstrup,et al.  Prenatally Fabricated Autologous Human Living Heart Valves Based on Amniotic Fluid–Derived Progenitor Cells as Single Cell Source , 2007, Circulation.

[28]  Marcel C M Rutten,et al.  Autologous Human Tissue-Engineered Heart Valves: Prospects for Systemic Application , 2006, Circulation.

[29]  F J Schoen,et al.  Functional Living Trileaflet Heart Valves Grown In Vitro , 2000, Circulation.

[30]  Artur Lichtenberg,et al.  Clinical Application of Tissue Engineered Human Heart Valves Using Autologous Progenitor Cells , 2006, Circulation.

[31]  D. Buttle,et al.  Improved quantitation and discrimination of sulphated glycosaminoglycans by use of dimethylmethylene blue. , 1986, Biochimica et biophysica acta.

[32]  John E Mayer,et al.  Endothelial progenitor and mesenchymal stem cell-derived cells persist in tissue-engineered patch in vivo: application of green and red fluorescent protein-expressing retroviral vector. , 2006, Tissue engineering.

[33]  Frederick J. Schoen,et al.  Evolving Concepts of Cardiac Valve Dynamics: The Continuum of Development, Functional Structure, Pathobiology, and Tissue Engineering , 2008, Circulation.

[34]  Paul Khairy,et al.  Bicuspid aortic valve morphology and interventions in the young. , 2007, Journal of the American College of Cardiology.