Creating the bioartificial myocardium for cardiac repair: challenges and clinical targets

Abstract

The association of stem cells with tissue-engineered scaffolds constitutes an attractive approach for the repair of myocardial tissue with positive effects to avoid ventricular chamber dilatation, which changes from a natural elliptical to spherical shape in heart failure patients. Biohybrid scaffolds using nanomaterials combined with stem cells emerge as new therapeutic tool for the creation of ‘bioartificial myocardium’ and ‘cardiac wrap bioprostheses’ for myocardial regeneration and ventricular support. Biohybrids are created introducing stem cells and self-assembling peptide nanofibers inside a porous elastomeric membrane, forming cell niches. Our studies lead to the creation of semi-degradable ‘ventricular support bioprostheses’ for adaptative LV and/or RV wrapping, designed with the concept of ‘helical myocardial bands’. The goal is to restore LV elliptical shape, and contribute to systolic contraction and diastolic filling (suction mechanism). Cardiac wrapping with ventricular bioprostheses may reduce the risk of heart failure progression and the indication for heart transplantation.

Keywords::

• bioartificial myocardium
• biohybrid scaffolds
• bionanomaterials
• cardiac bioregeneration
• cardiomyoplasty
• cell transplantation
• heart failure
• myocardial infarction
• myocardial regeneration
• tissue engineering

Acknowledgements

Our recognition for the scientific and technical collaboration to Nermine Lila, Julie Piquet, Adrien Lalot, Martine Rancic, Gwennhael Autret, Nicolas Mirochnik, David Bacquet (from Paris Team); Ana Valles, Cristina Martinez, Maria Arnal (from Valencia Team); Carol Soler, Carol Galvez, Laura Astier (from Badalona Team) and Teresa Fernandez Muiños, Cristina Castells, Joedmi Pereira (from Barcelona Team).

Financial & competing interests disclosure

The RECATABI PROJECT (Regeneration of Cardiac Tissue Assisted by Bioactive Implants) was financially supported by the 7th Framework Programme (FP7) of the European Commission. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Cardiac remodeling following myocardial infarction is one of the most common causes of heart failure (HF), cardiomyocyte death and scar formation modulate cardiac remodeling. Ischemic heart disease may progress inducing geometric alteration of the ventricular cavity, the original left ventricular (LV) elliptical chamber geometry becomes spherical. Heart dilatation is a negative symptom in the evolution of HF patients, related with morbidity and mortality. The underlying concept of rebuilding the ventricle by ventricular restoration is suggested to be reconstruction of form, rather than focusing on only the underlying disease.

• • Tissue engineering and nanobiomaterials (containing nanoparticles smaller than 100 nm) emerge as new therapeutic tool becoming a promising way for the creation of ‘bioartificial myocardium’. Biohybrid scaffolds are basically created introducing stem cells and self-assembling peptide nanofibers inside a porous elastomeric membrane. In this way, the membrane acts as carrier but most importantly, protects mechanically the cells into the soft nanofiber scaffold or hydrogel, creating cell niches.

• • Biohybrid scaffolds carrying stem cells embedded in a self-assembling nanofiber network demonstrated good cell survival, regular cell distribution and to properly deliver cells into the ischemic cardiac tissue of large animal models. The implanted stem cells started active migration into the host tissue suggesting that it could contribute to induce regeneration, angiogenesis and cardiac tissue neo-formation, improving systolic and diastolic functions, limiting therefore adverse remodeling of ventricular chambers.

• • Biohybrid scaffolds and nanobiotechnologies may contribute for the creation of cardiac wrap bioprostheses for myocardial regeneration and ventricular support that may reduce the risk of HF progression and cardiac death. Ventricular support bioprostheses could be indicated as a single procedure or following ventricular restoration surgery or the Revivent^™ myocardial anchoring system.

• • Ventricular support bioprostheses are designed with the concept of ‘helical myocardial bands’, following the anatomical heart configuration, where muscular ventricular bands provide conical configuration to LV chamber, beginning at the insertion of the pulmonary artery in the right ventricle and ending at the aortic valve annulus. For severe heart dilatation, double basal and apical ventricular helical loops are used. The role of myocardial band is to limit ventricular dilatation, preserving elliptical shape and contribute to systolic contraction and diastolic filling (suction mechanism). These myocardial bands may be repopulated with mesenchymal stem cells or cardiac contractile cells, afterward the construct might be electrically coupled to the host myocardium.

• • Stem cell differentiation can be achieved by extrinsic physical stimuli (electrostimulation, magnetic fields), cyclic compressive strain as well as by chemical (cytokines) and biological/genetic stimuli (cell co-cultures, genetic manipulations). Chronic electrostimulated MSC grafted in 3D scaffolds seems to be a way for the creation of bioartificial myocardium.

• • There is an increased demand for human organs to replace acute and chronically damaged tissues. This demand cannot be met by the currently available pool of donor organs. Efforts to provide an alternative source have led to the development of organ engineering, a discipline that combines progressive organ/matrix decellularization followed by cell perfusion for recellularization. These bioscaffolds can then be used to create potentially functional organs.

Notes

ECM: Extracellular matrix; MSC: Mesenchymal stem cell.

ECM: Extracellular matrix; HF: Heart failure.