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  • Review Article
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Next-generation tissue-engineered heart valves with repair, remodelling and regeneration capacity

Nature Reviews Cardiology volume 18, pages 92–116 (2021)Cite this article

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Abstract

Valvular heart disease is a major cause of morbidity and mortality worldwide. Surgical valve repair or replacement has been the standard of care for patients with valvular heart disease for many decades, but transcatheter heart valve therapy has revolutionized the field in the past 15 years. However, despite the tremendous technical evolution of transcatheter heart valves, to date, the clinically available heart valve prostheses for surgical and transcatheter replacement have considerable limitations. The design of next-generation tissue-engineered heart valves (TEHVs) with repair, remodelling and regenerative capacity can address these limitations, and TEHVs could become a promising therapeutic alternative for patients with valvular disease. In this Review, we present a comprehensive overview of current clinically adopted heart valve replacement options, with a focus on transcatheter prostheses. We discuss the various concepts of heart valve tissue engineering underlying the design of next-generation TEHVs, focusing on off-the-shelf technologies. We also summarize the latest preclinical and clinical evidence for the use of these TEHVs and describe the current scientific, regulatory and clinical challenges associated with the safe and broad clinical translation of this technology.

Key points

  • Surgical heart valve replacement is the gold-standard treatment for aortic valve disease, but transcatheter valve implantation has revolutionized the field by providing a novel treatment option for patients of all risk profiles.

  • Despite rapid advances in the field of heart valve therapy, an unmet clinical need remains for valve replacements with regenerative, remodelling and growth potential.

  • In situ tissue engineering technologies can be used to produce a heart valve replacement that is readily available, manufactured using decellularized extracellular matrix or bioresorbable polymers, and transforms into a native-equivalent valve after implantation.

  • Computational modelling is a powerful tool that can be used to improve and accelerate our understanding of tissue-engineered heart valve growth and remodelling and should be used in concert with in vitro and in vivo tissue engineering technologies.

  • To ensure the good clinical safety, feasibility and efficacy of the tissue-engineered heart valve, researchers and clinicians should work according to Good Manufacturing Practices and Good Laboratory Practices as well as to International Organization for Standardization requirements.

  • The field of heart valve tissue engineering still faces several challenges, such as issues related to immunocompatibility, haemocompatibility, remodelling and growth capacity, which need to be further investigated before broad clinical adoption is possible.

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Fig. 1: Evolution of heart valve replacement options.
Fig. 2: Overview of various tissue-engineered approaches.
Fig. 3: Challenges and future technologies for the successful generation of TEHVs.

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Acknowledgements

E.S.F. was supported by the Swiss National Science Foundation (PZ00P3_180138). M.Y.E. and S.L. have received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme, grant agreement no. 852814 (TAVI4Life) and grant agreement no. 802967 (MechanoSignaling).

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Author notes

  1. These authors contributed equally: Emanuela S. Fioretta, Sarah E. Motta.

Authors and Affiliations

  1. Institute for Regenerative Medicine, University of Zurich, Zurich, Switzerland

    Emanuela S. Fioretta, Sarah E. Motta, Simon P. Hoerstrup & Maximilian Y. Emmert

  2. Wyss Translational Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

    Sarah E. Motta, Valentina Lintas, Simon P. Hoerstrup & Maximilian Y. Emmert

  3. Disease Biophysics Group, John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA

    Sarah E. Motta & Kevin K. Parker

  4. Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands

    Sandra Loerakker & Frank P. T. Baaijens

  5. Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, Netherlands

    Sandra Loerakker

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

    Volkmar Falk & Maximilian Y. Emmert

  7. Department of Health Sciences and Technology, Swiss Federal Institute of Technology in Zurich, Zurich, Switzerland

    Volkmar Falk

  8. Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany

    Volkmar Falk & Maximilian Y. Emmert

  9. German Center of Cardiovascular Research, Partner Site Berlin, Berlin, Germany

    Volkmar Falk

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Contributions

E.S.F., S.E.M., V.L., S.L. and M.Y.E. wrote the manuscript and contributed substantially to discussion of its content. M.Y.E. developed the overall design and concept of the article. All the authors contributed to reviewing and editing the manuscript before submission.

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Correspondence to Maximilian Y. Emmert.

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Competing interests

F.P.T.B. and S.P.H. are shareholders at LifeMatrix and Xeltis. V.F. declares financial activities with Boston Scientific, Edwards Lifesciences and Medtronic in relation to educational grants (including travel support), fees for lectures and speeches, fees for professional consultation, and research and study funds. M.Y.E. is a shareholder at LifeMatrix. The other authors declare no competing interests.

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Glossary

Rheumatic fever

Inflammatory disease that mostly affects children aged 5–14 years and can cause permanent damage to the heart and heart valves.

Stenosis

Narrowing of the heart valve, which prevents proper opening, thereby reducing the blood flow through the valve.

Valve insufficiency

Also known as regurgitation or incompetence. Incomplete closure of the heart valve leaflets, which allows blood to flow backwards through the valve.

Annuloplasty

A procedure to tighten or reinforce the ring around a valve in the heart.

Bi-leaflet tilting disc

A valve made of a metal ring covered by polytetrafluoroethylene, whereby the metal ring holds a disc that opens and closes after one cardiac cycle.

Tetralogy of Fallot

A rare congenital condition caused by a combination of four heart defects: pulmonary valve stenosis, ventricular septal defect, overriding aorta and right ventricular hypertrophy.

Xenogeneic

Materials derived from tissues that originate from a different species to the recipient such as bovine pericardium or porcine valve leaflets.

Creep resistance

Refers to a solid material’s capacity to resist creep, that is, the tendency of a solid material to move slowly or deform over long-term exposure to high levels of stress.

Decellularization

To deplete cells from biological tissues in order to remove DNA and immunological epitopes. Decellularization can be performed via chemical, enzymatic or physical methods to ensure a cell-free material that is available off the shelf.

Functionalization

To include bioactive moieties, such as proteins, peptides and polysaccharides, into a scaffold by means of covalent or non-covalent binding to improve scaffold biocompatibility.

Crimping

A procedure used to reduce the diameter of the valve prosthesis by more than threefold to fit the prosthesis into the catheter used for minimally invasive implantation.

First-in-human

An early feasibility clinical study used to evaluate the initial clinical safety and performance in patients.

Valvuloplasty

Balloon valvuloplasty or balloon valvotomy is a procedure that repairs stenotic heart valves by expanding a balloon catheter inside the valve to increase the valve opening area.

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Fioretta, E.S., Motta, S.E., Lintas, V. et al. Next-generation tissue-engineered heart valves with repair, remodelling and regeneration capacity. Nat Rev Cardiol 18, 92–116 (2021). https://doi.org/10.1038/s41569-020-0422-8

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