1. 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

2. 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

3. 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 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.

4. Valve replacements Main drawback: no growth, repair and adaptation
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

5. 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.

6. 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

7. 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

8. 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

9. 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

10. Engineered tissues (In-vitro)

11. 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