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Bioengineering approaches to treat the failing heart: from cell biology to 3D printing

Abstract

Successfully engineering a functional, human, myocardial pump would represent a therapeutic alternative for the millions of patients with end-stage heart disease and provide an alternative to animal-based preclinical models. Although the field of cardiac tissue engineering has made tremendous advances, major challenges remain, which, if properly resolved, might allow the clinical implementation of engineered, functional, complex 3D structures in the future. In this Review, we provide an overview of state-of-the-art studies, challenges that have not yet been overcome and perspectives on cardiac tissue engineering. We begin with the most clinically relevant cell sources used in this field and discuss the use of topological, biophysical and metabolic stimuli to obtain mature phenotypes of cardiomyocytes, particularly in relation to organized cytoskeletal and contractile intracellular structures. We then move from the cellular level to engineering planar cardiac patches and discuss the need for proper vascularization and the main strategies for obtaining it. Finally, we provide an overview of several different approaches for the engineering of volumetric organs and organ parts — from whole-heart decellularization and recellularization to advanced 3D printing technologies.

Key points

  • The successful engineering of functional, human, myocardial tissues would represent a therapeutic alternative for the millions of patients with end-stage heart disease.

  • The well-organized, characteristic structure of the heart across its multiple scales is crucial for its mechanical function; therefore, recapitulating these structure–function relationships in engineered myocardial tissues is necessary.

  • Developing integrative maturation protocols and quantitative tools to assess the maturation of human induced pluripotent stem cell-derived cardiomyocytes is needed to produce cells with a mature phenotype that can successfully integrate with the host tissue.

  • Although the engineering of anisotropic, thick, vascularized tissue patches has been demonstrated using various fabrication techniques, their clinical implementation is still hampered by their poor integration with host tissue.

  • Fabricating 3D, volumetric, myocardial tissues could address the urgent need of patients with end-stage heart failure for heart donation and is therefore an active and evolving field of research.

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Fig. 1: Cardiac tissue engineering timeline.
Fig. 2: Cardiac tissue engineering concepts.
Fig. 3: Maturation of stem cell-derived cardiomyocytes.
Fig. 4: Recapitulating the native heart matrix.
Fig. 5: Approaches for tissue vascularization.
Fig. 6: Whole heart bioengineering: how to build a heart.
Fig. 7: Bioengineering ventricular-like structures and whole hearts.

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All the authors researched data for the article, provided substantial contributions to discussions of its content, wrote the article, and undertook review and/or editing of the manuscript before submission.

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Correspondence to Tal Dvir.

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Glossary

Anisotropy

A property of a material that allows it to show different characteristics in different directions, as opposed to isotropy. In this Review, we refer to the longitudinal alignment of the cells in one direction.

Micropatterning

Creating microscale patterns in a material or on its surface.

Surface functionalization

Altering the surface properties of a material to achieve specific function or activity, such as by binding cells or molecules.

Cyclic stretch

The application of periodic stretch–release cycles to cell-containing material to simulate the physiological mechanical strains that cells in the native heart experience.

Hydrogels

A crosslinked hydrophilic polymer that does not dissolve in water.

Melt electrospinning writing

A fabrication technique that uses polymer melts for controlled deposition of an electrospun fibre.

Conductive nanoparticles

Nano-scale particles possessing the physical property of being electrically conductive.

3D bioprinting

An additive manufacturing technique that uses cells and biocompatible materials as bio-inks to print living structures.

Photopolymerization

The polymerization or solidification of solubilized monomers by exposure to light, usually ultraviolet.

Stereolithography

A layer-by-layer 3D printing process whereby a photopolymer is selectively cured by a moving laser beam, causing a controlled, local crosslinking of the material.

Sacrificial writing

The process of printing structures using fugitive materials that will later dissolve, leaving empty spaces in the printed structure, as used for the bioprinting of blood vessels.

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Yadid, M., Oved, H., Silberman, E. et al. Bioengineering approaches to treat the failing heart: from cell biology to 3D printing. Nat Rev Cardiol 19, 83–99 (2022). https://doi.org/10.1038/s41569-021-00603-7

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