Anita Mol, Carlijn Bouten, Simon Hoerstrup, Regenerative Medicine Anita Mol, Carlijn Bouten, Simon Hoerstrup, Frank Baaijens Laboratory for Tissue Biomechanics and Tissue Engineering, Department of Biomedical Engineering, Eindhoven University of Technology

Healthcare-transforming technologies Minimally Invasive surgery Reducing patient trauma and reduces costs Imaging Earlier diagnosis saves lives and reduces costs Clinical IT Right Information at the right time enables best treatment and reduces costs Molecular Medicine Preventing disease from happening and reduces costs Regenerative medicine Implants taking over vital bodily functions, improving quality of life Adapted from: Russ Coile, Futurescan 2003, SG-2

Heart valves The aortic heart valve is one of the four valves in the heart. It is situated at the outlet of the left ventricle and controls the unidirectional blood flow from the ventricle to the aorta. The valve consists of three leaflets, three sinuses and the aortic ring, which forms the line of attachment of the leaflets to the aortic wall. The leaflets form cusps that closely fit together during closure of the valve The valve opens and closes about 105.000 times a day and 3.7 billion times in a lifetime and you can imagine that this requires strength, durability and flexibility of the tissue. Pathological changes due to congenital abnormalities, rheumatic fever, or calcification may result in stenosis, (restriction of the opening of the valve), or insufficient closure, causing back flow or regurgitation. These conditions increase the workload for the heart and compromise cardiac function. In severe cases heart valve dysfunction is treated with replacement of the valve with a prosthesis.

Valve replacements Main drawback: no growth, repair and adaptation 300.000 replacements / year The annual number of heart valve replacements is 170 thousand. Currently used prostheses used are either artificial or biological in nature. As you will probably know mechanical valves, like the tilting disk or bileaflet valves, are time resistant but trombogenic and require life long anticoagulation therapy. Main drawback: no growth, repair and adaptation

Tissue Engineering Paradigm Cells Scaffold (Mechanical) preconditioning Tissue formation, matrix remodelling Implantation/ Model system Implantation Isolation of cells from vessels Seeding in scaffold Culture, conditioning Tissue formation vsmc endothelial cells To overcome this problem tissue engineered heart valves are being developed. Above you see the general roadmap for tissue engineering, below specific protocols for heart valve engineering. These valves consist of autologous cells, for instance isolated from blood vessels, which are seeded on a biodegradable scaffold with the typical valve geometry and cultured under conditions that mimic the physiological in-vivo environment. This is typically done in a so-called bioreactor. The scaffold provides initial anchorage and support for the cells, until they have produced and reorganized their own extracellular matrix to form a functional tissue. By that time, ideally, the scaffold should be fully degraded to obtain a completely autologous valve. This may be achieved before or after implantation.

Proof-of-concept: sheep cells Hoerstrup et al. Circulation 2000 Implanted as pulmonary heart valve replacement 6 weeks 16 weeks 20 weeks Not sufficient load-bearing properties to serve as aortic valve replacement

Challenge Develop a living, autologous valve replacement, able to grow, repair and adapt to changing environment using human cells Sufficiently strong for aortic (high pressure) side

Effective orifice area: Mean systolic gradient: Strong, functional human valves! Mol et al. Circulation 2006 Effective orifice area: 1.52  0.21 cm2 Mean systolic gradient: 11.5  3.1 mm Hg Regurgitation: 18.2  4.2 % Dynamically conditioned tissue engineered human heart valve

Discussion Tissue engineered human heart valves show promising features as aortic valve replacements Functional parameters are in the range of those reported for commonly used bioprostheses Upcoming animal studies will elucidate short- and long-term functionality of tissue-engineered heart valves in aortic position and the capability of growth and remodeling

Engineered tissues (In-vitro)

Acknowledgements Eindhoven, BMT, TBME Eindhoven, BMT / ST, SMO Dr. Anita Mol Drs. Marjolein van Lieshout Ir. Niels Driessen Ir. Ralf Boerboom Ir. Angelique Balguid Ir. Rolf Pullens Ir. Martijn Cox Ir. Mirjam Rubbens Christa Dam Katy Krahn Dr. Carlijn Bouten Dr. Marcel Rutten Dr. Claudia Vaz Dr. Gerrit Peeters Prof. Bas de Mol Prof. Frank Baaijens Eindhoven, BMT / ST, SMO Ir. Eva Wisse Drs. Patricia Dankers Dr. Nico Sommerdijk Dr. Maarten Merkx Prof. Bert Meijer Eindhoven, BMT, BEMI Prof. Klaas Nicolaij Dr. Gustav Strijkers Zürich Dr. Stephan Neuenschwander Dörthe Schmidt, MSc. Prof. Simon Hoerstrup Leiden, TNO TPG Dr. Ruud Bank Rotterdam, Dutch Heart Valve Bank Dr. J. van Kats, prof. A. Bogers Grants Bio-Initiative, Eindhoven University of Technology Vici grant, Netherlands Organisation for Scientific Research BioPolymers program, Dutch Polymer Institute