166
material compatibility, sterility requirements, incubator compatibility, and the integration of sensors, must all be considered in selecting the appropriate system for a
particular application.
6.7 Conclusions
Multicellular systems have been developed to mimic the native myocardium and
prolong survival of cardiac grafts when implanted in vivo. Several strategies utilizing simultaneous seeding, sequential seeding, and the combination of vascularized
and cardiac constructs have been explored to achieve fully vascularized, contractile
grafts. While a complete human system will be critical to the clinical translation of
this technology, there are important questions surrounding the maturation of pluripotent stem cell-derived cardiomyocytes that must be addressed. Several techniques are under investigation, to improve the maturation of those cells and the
overall organization and functionality of engineering cardiac grafts, including electrical stimulation, mechanical stimulation, and a combination of electromechanical
stimulation. Recent developments have greatly improved the physiological relevance and translational potential of engineered cardiac patches, but further applications will hinge on the incorporation of dense, functional vasculature and
co-alignment of cardiomyocytes.
References
1. Alberti, K., Davey, R. E., Onishi, K., George, S., Salchert, K., Seib, F. P., et al. (2008).
Functional immobilization of signaling proteins enables control of stem cell fate. Nature
Methods, 5(7), 645–650. https://doi.org/10.1038/nmeth.1222
2. Allen, P., Melero-Martin, J., & Bischoff, J. (2011). Type I collagen, fibrin and PuraMatrix
matrices provide permissive environments for human endothelial and mesenchymal progenitor cells to form neovascular networks. Journal of Tissue Engineering and Regenerative
Medicine, 5(4), 1–18. https://doi.org/10.1002/term.389
3. Alt, E., Yan, Y., Gehmert, S., Song, Y. H., Altman, A., Gehmert, S., et al. (2011). Fibroblasts
share mesenchymal phenotypes with stem cells, but lack their differentiation and colonyforming potential. Biology of the Cell, 103(4), 197–208. https://doi.org/10.1042/BC20100117
4. Bai, H., Forrester, J. V., & Zhao, M. (2015). DC electric stimulation upregulates angiogenic
factors in endothelial cells through activation of VEGF receptors. Cytokine, 55(1), 110–115.
https://doi.org/10.1016/j.cyto.2011.03.003
5. Baker, L. L., Chambers, R., DeMuth, S. K., & Villar, F. (1997). Effects of electrical stimulation on wound healing in patients with diabetic ulcers. Diabetes Care, 20, 405–412.
6. Baum, J., & Duffy, H. S. (2011). Fibroblasts and myofibroblasts: What are we talking
about? Journal of Cardiovascular Pharmacology, 57(4), 376–379. https://doi.org/10.1097/
FJC.0b013e3182116e39
7. Benjamin, E. J., Blaha, M. J., Chiuve, S. E., Cushman, M., Das, S. R., Deo, R., et al.
(2017). Heart disease and stroke statistics-2017 update: A report from the American Heart
Association. Circulation, 135, e146. https://doi.org/10.1161/CIR.0000000000000485
J. Morrissette-McAlmon et al.
material compatibility, sterility requirements, incubator compatibility, and the integration of sensors, must all be considered in selecting the appropriate system for a
particular application.
6.7 Conclusions
Multicellular systems have been developed to mimic the native myocardium and
prolong survival of cardiac grafts when implanted in vivo. Several strategies utilizing simultaneous seeding, sequential seeding, and the combination of vascularized
and cardiac constructs have been explored to achieve fully vascularized, contractile
grafts. While a complete human system will be critical to the clinical translation of
this technology, there are important questions surrounding the maturation of pluripotent stem cell-derived cardiomyocytes that must be addressed. Several techniques are under investigation, to improve the maturation of those cells and the
overall organization and functionality of engineering cardiac grafts, including electrical stimulation, mechanical stimulation, and a combination of electromechanical
stimulation. Recent developments have greatly improved the physiological relevance and translational potential of engineered cardiac patches, but further applications will hinge on the incorporation of dense, functional vasculature and
co-alignment of cardiomyocytes.
References
1. Alberti, K., Davey, R. E., Onishi, K., George, S., Salchert, K., Seib, F. P., et al. (2008).
Functional immobilization of signaling proteins enables control of stem cell fate. Nature
Methods, 5(7), 645–650. https://doi.org/10.1038/nmeth.1222
2. Allen, P., Melero-Martin, J., & Bischoff, J. (2011). Type I collagen, fibrin and PuraMatrix
matrices provide permissive environments for human endothelial and mesenchymal progenitor cells to form neovascular networks. Journal of Tissue Engineering and Regenerative
Medicine, 5(4), 1–18. https://doi.org/10.1002/term.389
3. Alt, E., Yan, Y., Gehmert, S., Song, Y. H., Altman, A., Gehmert, S., et al. (2011). Fibroblasts
share mesenchymal phenotypes with stem cells, but lack their differentiation and colonyforming potential. Biology of the Cell, 103(4), 197–208. https://doi.org/10.1042/BC20100117
4. Bai, H., Forrester, J. V., & Zhao, M. (2015). DC electric stimulation upregulates angiogenic
factors in endothelial cells through activation of VEGF receptors. Cytokine, 55(1), 110–115.
https://doi.org/10.1016/j.cyto.2011.03.003
5. Baker, L. L., Chambers, R., DeMuth, S. K., & Villar, F. (1997). Effects of electrical stimulation on wound healing in patients with diabetic ulcers. Diabetes Care, 20, 405–412.
6. Baum, J., & Duffy, H. S. (2011). Fibroblasts and myofibroblasts: What are we talking
about? Journal of Cardiovascular Pharmacology, 57(4), 376–379. https://doi.org/10.1097/
FJC.0b013e3182116e39
7. Benjamin, E. J., Blaha, M. J., Chiuve, S. E., Cushman, M., Das, S. R., Deo, R., et al.
(2017). Heart disease and stroke statistics-2017 update: A report from the American Heart
Association. Circulation, 135, e146. https://doi.org/10.1161/CIR.0000000000000485
J. Morrissette-McAlmon et al.