Abstract
Despite great progress in engineering functional tissues for organ repair, including the heart, an invasive surgical approach is still required for their implantation. Here, we designed an elastic and microfabricated scaffold using a biodegradable polymer (poly(octamethylene maleate (anhydride) citrate)) for functional tissue delivery via injection. The scaffold’s shape memory was due to the microfabricated lattice design. Scaffolds and cardiac patches (1 cm × 1 cm) were delivered through an orifice as small as 1 mm, recovering their initial shape following injection without affecting cardiomyocyte viability and function. In a subcutaneous syngeneic rat model, injection of cardiac patches was equivalent to open surgery when comparing vascularization, macrophage recruitment and cell survival. The patches significantly improved cardiac function following myocardial infarction in a rat, compared with the untreated controls. Successful minimally invasive delivery of human cell-derived patches to the epicardium, aorta and liver in a large-animal (porcine) model was achieved.
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References
Zimmermann, W. H. et al. Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts. Nat. Med. 12, 452–458 (2006).
Kurobe, H., Maxfield, M. W., Breuer, C. K. & Shinoka, T. Concise review: tissue-engineered vascular grafts for cardiac surgery: past, present, and future. Stem Cells Transl. Med. 1, 566–571 (2012).
Moreira-Teixeira, L. S., Georgi, N., Leijten, J., Wu, L. & Karperien, M. Cartilage and Bone Development and its Disorders Vol. 21 102–115 (Karger Publishers, 2011).
Bose, S., Roy, M. & Bandyopadhyay, A. Recent advances in bone tissue engineering scaffolds. Trends Biotechnol. 30, 546–554 (2012).
Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013).
Karamichos, D. Ocular tissue engineering: current and future directions. J. Funct. Biomater. 6, 77–80 (2015).
Iso, Y. et al. Multipotent human stromal cells improve cardiac function after myocardial infarction in mice without long-term engraftment. Biochem. Biophys. Res. Commun. 354, 700–706 (2007).
Zeng, L. et al. Bioenergetic and functional consequences of bone marrow-derived multipotent progenitor cell transplantation in hearts with postinfarction left ventricular remodeling. Circulation 115, 1866–1875 (2007).
Hasan, A. et al. Injectable hydrogels for cardiac tissue repair after myocardial infarction. Adv. Sci. 2, 1500122 (2015).
Müller-Ehmsen, J. et al. Survival and development of neonatal rat cardiomyocytes transplanted into adult myocardium. J. Mol. Cell. Cardiol. 34, 107–116 (2002).
Huyer, L. D. et al. Biomaterial based cardiac tissue engineering and its applications. Biomed. Mater. 10, 034004 (2015).
Tokunaga, M. et al. Implantation of cardiac progenitor cells using self-assembling peptide improves cardiac function after myocardial infarction. J. Mol. Cell Cardiol. 49, 972–983 (2010).
Sawa, Y. et al. Tissue engineered myoblast sheets improved cardiac function sufficiently to discontinue LVAS in a patient with DCM: report of a case. Surg. Today 42, 181–184 (2012).
Bencherif, S. A. et al. Injectable preformed scaffolds with shape-memory properties. Proc. Natl Acad. Sci. USA 109, 19590–19595 (2012).
Wang, L. et al. Minimally invasive approach to the repair of injured skeletal muscle with a shape-memory scaffold. Mol. Ther. 22, 1441–1449 (2014).
Hardy, J. G., Palma, M., Wind, S. J. & Biggs, M. J. Responsive biomaterials: advances in materials based on shape-memory polymers. Adv. Mater. 28, 5717–5724 (2016).
Zhang, B. et al. Biodegradable scaffold with built-in vasculature for organ-on-a-chip engineering and direct surgical anastomosis. Nat. Mater. 15, 669–678 (2016).
Zhang, B., Montgomery, M., Davenport-Huyer, L., Korolj, A. & Radisic, M. Platform technology for scalable assembly of instantaneously functional mosaic tissues. Sci. Adv. 1, e1500423 (2015).
Chiu, L. L., Janic, K. & Radisic, M. Engineering of oriented myocardium on three-dimensional micropatterned collagen-chitosan hydrogel. Int. J. Artif Organs 35, 237–250 (2012).
Nunes, S. S. et al. Biowire: a platform for maturation of human pluripotent stem cell-derived cardiomyocytes. Nat. Methods 10, 781–787 (2013).
Engelmayr, G. C. Jr et al. Accordion-like honeycombs for tissue engineering of cardiac anisotropy. Nat. Mater. 7, 1003–1010 (2008).
Holmes, J. W., Borg, T. K. & Covell, J. W. Structure and mechanics of healing myocardial infarcts. Annu. Rev. Biomed. Eng. 7, 223–253 (2005).
Pacher, P., Nagayama, T., Mukhopadhyay, P., Batkai, S. & Kass, D. A. Measurement of cardiac function using pressure–volume conductance catheter technique in mice and rats. Nat. Protoc. 3, 1422–1434 (2008).
Chong, J. J. et al. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature 510, 273–277 (2014).
Iaizzo, P. A. Handbook of Cardiac Anatomy, Physiology, and Devices (Humana Press, 2005).
Jackson, P. G. & Cockcroft, P. D. Handbook of Pig Medicine (Elsevier Health Sciences, 2007).
van der Spoel, T. I. et al. Human relevance of pre-clinical studies in stem cell therapy: systematic review and meta-analysis of large animal models of ischaemic heart disease. Cardiovasc. Res. 91, 649–658 (2011).
Chiu, L. L. & Radisic, M. Cardiac tissue engineering. Curr. Opin. Chem. Eng. 2, 41–52 (2013).
Menasche, P. et al. Human embryonic stem cell-derived cardiac progenitors for severe heart failure treatment: first clinical case report. Eur. Heart J. 36, 2011–2017 (2015).
Freed, L. E., Engelmayr, G. C. Jr, Borenstein, J. T., Moutos, F. T. & Guilak, F. Advanced material strategies for tissue engineering scaffolds. Adv. Mater. 21, 3410–3418 (2009).
Omens, J. H. Stress and strain as regulators of myocardial growth. Prog. Biophys. Mol. Biol. 69, 559–572 (1998).
Jacot, J. G., McCulloch, A. D. & Omens, J. H. Substrate stiffness affects the functional maturation of neonatal rat ventricular myocytes. Biophys. J. 95, 3479–3487 (2008).
Tran, R. T. et al. Synthesis and characterization of a biodegradable elastomer featuring a dual crosslinking mechanism. Soft Matter 6, 2449–2461 (2010).
Jiang, F. et al. Neovascularization in an arterio-venous loop-containing tissue engineering chamber: role of NADPH oxidase. J. Cell. Mol. Med. 12, 2062–2072 (2008).
Spiller, K. L., Freytes, D. O. & Vunjak-Novakovic, G. Macrophages modulate engineered human tissues for enhanced vascularization and healing. Ann. Biomed. Eng. 43, 616–627 (2015).
Ye, L. et al. Cardiac repair in a porcine model of acute myocardial infarction with human induced pluripotent stem cell-derived cardiovascular cells. Cell Stem Cell 15, 750–761 (2014).
Laflamme, M. A. et al. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat. Biotechnol. 25, 1015–1024 (2007).
Chiu, L. L., Montgomery, M., Liang, Y., Liu, H. & Radisic, M. Perfusable branching microvessel bed for vascularization of engineered tissues. Proc. Natl Acad. Sci. USA 109, E3414–E3423 (2012).
Davenport Huyer, L. et al. Highly elastic and moldable polyester biomaterial for cardiac tissue engineering applications. ACS Biomater. Sci. Eng. 2, 780–788 (2016).
Kan, C. D., Li, S. H., Weisel, R. D., Zhang, S. & Li, R. K. Recipient age determines the cardiac functional improvement achieved by skeletal myoblast transplantation. J. Am. Coll. Cardiol. 50, 1086–1092 (2007).
Acknowledgements
This work was funded by the Canadian Institutes of Health Research (CIHR) Operating Grant MOP-137107, the National Sciences and Engineering Research Council of Canada (NSERC) Steacie Fellowship to M.R., University of Toronto McLean Award to M.R., NSERC Vanier Scholarship to M.M., Training Program in Organ-on-a-Chip Engineering & Entrepreneurship (TOeP) NSERC CREATE Scholarship to M.M., the CIHR Operating Grant (MOP-126027), the Heart and Stroke Foundation Grant G-16-00012711, NSERC Discovery Grant (RGPIN-2015-05952), Canada Foundation for Innovation Grant (226225) and Ontario Institute for Regenerative Medicine New Ideas Grant (500235). The authors acknowledge the Canada Foundation for Innovation, Project 19119, and the Ontario Research Fund for funding of the Centre for Spectroscopic Investigation of Complex Organic Molecules and Polymers. Some of the equipment used in this study was supported by the 3D (Diet, Digestive Tract and Disease) Centre funded by the Canadian Foundation for Innovation and Ontario Research Fund, project number 19442 and 30961. The assistance in bioluminescence imaging provided by A. Hardy of the CFI 3D facility is highly acknowledged. We thank L. You from the Department of Mechanical and Industrial Engineering at the University of Toronto for offering expertise in reviewing the FEA simulation data, and B. Zhang and A. Korolj in helping review and provide comments on the manuscript.
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Contributions
M.M. and M.R. conceived the idea, designed the experiments and analysed the results. M.M. and S.Ahadian performed the experiments and analysed the results. M.M. and L.D.H. synthesized and characterized the POMAC prepolymer. L.D.H. assisted in animal models. M.L.R., R.D.V. and C.A.C. developed and executed the porcine model and wrote the corresponding method section. R.A.C. assisted in cell culture, porcine experiments and histology sample preparation. L.A.R. assisted in experiments and analysing the results. S.Akbari performed the FEA. A.P. cultured and differentiated human stem cells. J.W. and R.-K.L. performed the functional myocardial infarction study. A.M. performed the surgical placement of scaffolds onto the rat heart in the host response study. M.M., S.Ahadian and M.R. wrote the manuscript. M.R. supervised the entire project. All authors read the manuscript, commented on it and approved its content.
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Montgomery, M., Ahadian, S., Davenport Huyer, L. et al. Flexible shape-memory scaffold for minimally invasive delivery of functional tissues. Nature Mater 16, 1038–1046 (2017). https://doi.org/10.1038/nmat4956
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DOI: https://doi.org/10.1038/nmat4956
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