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Development of a Novel Human Cell-Derived Tissue-Engineered Heart Valve for Transcatheter Aortic Valve Replacement: an In Vitro and In Vivo Feasibility Study

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Abstract

Transcatheter aortic valve replacement (TAVR) is being extended to younger patients. However, TAVR-compatible bioprostheses are based on xenogeneic materials with limited durability. Off-the-shelf tissue-engineered heart valves (TEHVs) with remodeling capacity may overcome the shortcomings of current TAVR devices. Here, we develop for the first time a TEHV for TAVR, based on human cell-derived extracellular matrix and integrated into a state-of-the-art stent for TAVR. The TEHVs, characterized by a dense acellular collagenous matrix, demonstrated in vitro functionality under aortic pressure conditions (n = 4). Next, transapical TAVR feasibility and in vivo TEHV functionality were assessed in acute studies (n = 5) in sheep. The valves successfully coped with the aortic environment, showing normal leaflet motion, free coronary flow, and absence of stenosis or paravalvular leak. At explantation, TEHVs presented full structural integrity and initial cell infiltration. Its long-term performance proven, such TEHV could fulfill the need for next-generation lifelong TAVR prostheses.

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Abbreviations

3D-CT:

Three-dimensional computer tomography

Col-1:

Collagen-1

Col-3:

Collagen-3

DNA:

Deoxyribonucleic acid

ECM:

Extracellular matrix

ELVG:

Elastica van Gieson

GAGs:

Glycosaminoglycans

H&E:

Hematoxylin and eosin

Hyp:

Hydroxyproline

PBS:

Phosphate-buffered saline

SRS:

Suture retention strength

TAVR:

Transcatheter aortic valve replacement

TEE:

Transesophageal echocardiography

TEHV:

Tissue-engineered heart valve

TGF-β1:

Transforming growth factor-beta1

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Funding

This work was supported by the Swiss Heart Foundation (grant agreement no. 75010) and by the Forschungskredit Candoc program of the University of Zurich (grant agreement no. F-43010-02-01).

Author information

Authors and Affiliations

  1. Institute for Regenerative Medicine (IREM), University of Zurich, Center for Therapy Development/GMP, Zurich, Switzerland

    V. Lintas, E. S. Fioretta, S. E. Motta, P. E. Dijkman, S. P. Hoerstrup & M. Y. Emmert

  2. Institute for Mechanical Systems, Department of Mechanical and Process Engineering, ETH Zurich, Zurich, Switzerland

    M. Pensalfini & E. Mazza

  3. Clinic for Cardiac Surgery, University Hospital Zurich, Zurich, Switzerland

    E. Caliskan, H. Rodriguez, M. Lipiski, M. Sauer, N. Cesarovic & M. Y. Emmert

  4. Department of Cardiovascular Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany

    E. Caliskan

  5. Department of Cardiothoracic and Vascular Surgery, German Heart Institute Berlin, Berlin, Germany

    E. Caliskan

  6. Department of Surgical Research, University Hospital Zurich-University of Zurich, Zurich, Switzerland

    M. Y. Emmert

  7. Wyss Translational Center Zurich, University and ETH Zurich, Zürich, Switzerland

    M. Y. Emmert

Authors
  1. V. Lintas
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  2. E. S. Fioretta
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  3. S. E. Motta
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  4. P. E. Dijkman
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  5. M. Pensalfini
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  6. E. Mazza
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  7. E. Caliskan
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  8. H. Rodriguez
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  9. M. Lipiski
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  10. M. Sauer
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  11. N. Cesarovic
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  12. S. P. Hoerstrup
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  13. M. Y. Emmert
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Corresponding author

Correspondence to M. Y. Emmert.

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Conflict of Interest

The authors declare that they have no conflicts of interest.

Ethical Approval for Research Involving Animals

All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the appropriate institutional committees. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Ethical Approval for Research Involving Humans

This article does not contain any studies with human participants performed by any of the authors.

Clinical Relevance of the Study

Nowadays, all TAVR prostheses are based on non-regenerative glutaraldehyde-fixed xenomaterials and are susceptible to structural tissue degeneration. The short lifespan of current TAVR devices requires repeated interventions over the patient’s lifetime and hence questioning the expansion of TAVR to younger patients. Given proof of their long-term remodeling and functionality as aortic valve substitutes, off-the-shelf, TAVR-compatible TEHVs with self-repair capacity would overcome the shortcomings of current TAVR devices and offer durable, regenerative prostheses for treating adult and young patients.

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Associate Editor Enrique Lara-Pezzi oversaw the review of this article

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Lintas, V., Fioretta, E.S., Motta, S.E. et al. Development of a Novel Human Cell-Derived Tissue-Engineered Heart Valve for Transcatheter Aortic Valve Replacement: an In Vitro and In Vivo Feasibility Study. J. of Cardiovasc. Trans. Res. 11, 470–482 (2018). https://doi.org/10.1007/s12265-018-9821-1

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