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A tissue-engineered scale model of the heart ventricle

Nature Biomedical Engineering volume 2, pages 930–941 (2018)Cite this article

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An Addendum to this article was published on 08 March 2022

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Abstract

Laboratory studies of the heart use cell and tissue cultures to dissect heart function yet rely on animal models to measure pressure and volume dynamics. Here, we report tissue-engineered scale models of the human left ventricle, made of nanofibrous scaffolds that promote native-like anisotropic myocardial tissue genesis and chamber-level contractile function. Incorporating neonatal rat ventricular myocytes or cardiomyocytes derived from human induced pluripotent stem cells, the tissue-engineered ventricles have a diastolic chamber volume of ~500 µl (comparable to that of the native rat ventricle and approximately 1/250 the size of the human ventricle), and ejection fractions and contractile work 50–250 times smaller and 104–108 times smaller than the corresponding values for rodent and human ventricles, respectively. We also measured tissue coverage and alignment, calcium-transient propagation and pressure–volume loops in the presence or absence of test compounds. Moreover, we describe an instrumented bioreactor with ventricular-assist capabilities, and provide a proof-of-concept disease model of structural arrhythmia. The model ventricles can be evaluated with the same assays used in animal models and in clinical settings.

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Fig. 1: Tissue-engineered model ventricles recapitulate key structural and functional aspects of natural ventricular myocardium.
Fig. 2: Tissue-engineered ventricle immunostaining.
Fig. 3: Intraventricular PV data obtained by tissue-engineered ventricle catheterization.
Fig. 4: A HBR for tissue-engineered ventricle culture, assisted contraction and instrumentation.
Fig. 5: Structural arrhythmia disease model.

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  • 27 July 2018

    In the version of this Article originally published, the links to Supplementary Videos 1–15 went to the wrong files; the links have now been corrected.

References

  1. Benam, K. H. et al. Engineered in vitro disease models. Annu Rev. Pathol. 10, 195–262 (2015).

    CAS  PubMed  Google Scholar 

  2. Tzatzalos, E., Abilez, O. J., Shukla, P. & Wu, J. C. Engineered heart tissues and induced pluripotent stem cells: macro- and microstructures for disease modeling, drug screening, and translational studies. Adv. Drug Deliv. Rev. 96, 234–244 (2016).

    CAS  PubMed  Google Scholar 

  3. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Ram, R., Mickelsen, D. M., Theodoropoulos, C. & Blaxall, B. C. New approaches in small animal echocardiography: imaging the sounds of silence. Am. J. Physiol. Heart Circ. Physiol. 301, H1765–1780 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Bakermans, A. J. et al. Small animal cardiovascular MR imaging and spectroscopy. Prog. Nucl. Magn. Reson. Spectrosc. 88–89, 1–47 (2015).

    PubMed  Google Scholar 

  6. Chandrasekera, P. C. & Pippin, J. J. The human subject: an integrative animal model for 21st century heart failure research. Am. J. Transl. Res. 7, 1636–1647 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Gloschat, C. R. et al. Arrhythmogenic and metabolic remodelling of failing human heart. J. Physiol. 594, 3963–3980 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Karakikes, I., Ameen, M., Termglinchan, V. & Wu, J. C. Human induced pluripotent stem cell-derived cardiomyocytes: insights into molecular, cellular, and functional phenotypes. Circ. Res. 117, 80–88 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Feric, N. T. & Radisic, M. Maturing human pluripotent stem cell-derived cardiomyocytes in human engineered cardiac tissues. Adv. Drug Deliv. Rev. 96, 110–134 (2016).

    CAS  PubMed  Google Scholar 

  10. Eder, A., Vollert, I., Hansen, A. & Eschenhagen, T. Human engineered heart tissue as a model system for drug testing. Adv. Drug Deliv. Rev. 96, 214–224 (2016).

    CAS  PubMed  Google Scholar 

  11. Wang, G. et al. Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. Nat. Med. 20, 616–623 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Lind, J. U. et al. Instrumented cardiac microphysiological devices via multimaterial three-dimensional printing. Nat. Mater. 16, 303–308 (2017).

    CAS  PubMed  Google Scholar 

  13. Boudou, T. et al. A microfabricated platform to measure and manipulate the mechanics of engineered cardiac microtissues. Tissue Eng. Part A 18, 910–919 (2012).

    CAS  PubMed  Google Scholar 

  14. Nunes, S. S. et al. Biowire: a platform for maturation of human pluripotent stem cell-derived cardiomyocytes. Nat. Methods 10, 781–787 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Thavandiran, N. et al. Design and formulation of functional pluripotent stem cell-derived cardiac microtissues. Proc. Natl Acad. Sci. USA 110, E4698–4707 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Mannhardt, I. et al. Human engineered heart tissue: analysis of contractile force. Stem Cell Rep. 7, 29–42 (2016).

    CAS  Google Scholar 

  17. Huebsch, N. et al. Miniaturized iPS-cell-derived cardiac muscles for physiologically relevant drug response analyses. Sci. Rep. 6, 24726 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Mathur, A. et al. Human iPSC-based cardiac microphysiological system for drug screening applications. Sci. Rep. 5, 8883 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Turnbull, I. C. et al. Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium. FASEB J. 28, 644–654 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Sidorov, V. Y. et al. I-Wire Heart-on-a-Chip I: three-dimensional cardiac tissue constructs for physiology and pharmacology. Acta Biomater. 48, 68–78 (2017).

    CAS  PubMed  Google Scholar 

  21. Godier-Furnemont, A. F. G. et al. Physiologic force–frequency response in engineered heart muscle by electromechanical stimulation. Biomaterials 60, 82–91 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Tiburcy, M. et al. Defined engineered human myocardium with advanced maturation for applications in heart failure modelling and repair. Circulation 135, 1832–1847 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Mathur, A., Ma, Z., Loskill, P., Jeeawoody, S. & Healy, K. E. In vitro cardiac tissue models: current status and future prospects. Adv. Drug Deliv. Rev. 96, 203–213 (2016).

    CAS  PubMed  Google Scholar 

  24. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Burkhoff, D., Mirsky, I. & Suga, H. Assessment of systolic and diastolic ventricular properties via pressure–volume analysis: a guide for clinical, translational, and basic researchers. Am. J. Physiol. Heart Circ. Physiol. 289, H501–512 (2005).

    CAS  PubMed  Google Scholar 

  26. Lee, E. J., Kim do, E., Azeloglu, E. U. & Costa, K. D. Engineered cardiac organoid chambers: toward a functional biological model ventricle. Tissue Eng. Part A 14, 215–225 (2008).

    CAS  PubMed  Google Scholar 

  27. Gonen-Wadmany, M., Gepstein, L. & Seliktar, D. Controlling the cellular organization of tissue-engineered cardiac constructs. Ann. N. Y. Acad. Sci. 1015, 299–311 (2004).

    PubMed  Google Scholar 

  28. Yildirim, Y. et al. Development of a biological ventricular assist device: preliminary data from a small animal model. Circulation 116, I-16–I-23 (2007).

    Google Scholar 

  29. Li, R. A. et al. Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells. Biomaterials 163, 116–127 (2018).

    PubMed  PubMed Central  Google Scholar 

  30. Costa, K. D., Takayama, Y., McCulloch, A. D. & Covell, J. W. Laminar fiber architecture and three-dimensional systolic mechanics in canine ventricular myocardium. Am. J. Physiol. 276, H595–607 (1999).

    CAS  PubMed  Google Scholar 

  31. Arts, T., Costa, K. D., Covell, J. W. & McCulloch, A. D. Relating myocardial laminar architecture to shear strain and muscle fiber orientation. Am. J. Physiol. Heart Circ. Physiol. 280, H2222–2229 (2001).

    CAS  PubMed  Google Scholar 

  32. Rohr, S., Scholly, D. M. & Kleber, A. G. Patterned growth of neonatal rat heart cells in culture. Morphological and electrophysiological characterization. Circ. Res. 68, 114–130 (1991).

    CAS  PubMed  Google Scholar 

  33. Kleber, A. G. & Rudy, Y. Basic mechanisms of cardiac impulse propagation and associated arrhythmias. Physiol. Rev. 84, 431–488 (2004).

    CAS  PubMed  Google Scholar 

  34. Bursac, N., Parker, K. K., Iravanian, S. & Tung, L. Cardiomyocyte cultures with controlled macroscopic anisotropy: a model for functional electrophysiological studies of cardiac muscle. Circ. Res. 91, e45–54 (2002).

    CAS  PubMed  Google Scholar 

  35. Feinberg, A. W. et al. Controlling the contractile strength of engineered cardiac muscle by hierarchal tissue architecture. Biomaterials 33, 5732–5741 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Zong, X. et al. Electrospun fine-textured scaffolds for heart tissue constructs. Biomaterials 26, 5330–5338 (2005).

    CAS  PubMed  Google Scholar 

  37. Kai, D., Prabhakaran, M. P., Jin, G. & Ramakrishna, S. Guided orientation of cardiomyocytes on electrospun aligned nanofibers for cardiac tissue engineering. J. Biomed. Mater. Res B Appl. Biomater. 98, 379–386 (2011).

    PubMed  Google Scholar 

  38. Kenar, H., Kose, G. T., Toner, M., Kaplan, D. L. & Hasirci, V. A 3D aligned microfibrous myocardial tissue construct cultured under transient perfusion. Biomaterials 32, 5320–5329 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Orlova, Y., Magome, N., Liu, L., Chen, Y. & Agladze, K. Electrospun nanofibers as a tool for architecture control in engineered cardiac tissue. Biomaterials 32, 5615–5624 (2011).

    CAS  PubMed  Google Scholar 

  40. Capulli, A. K., MacQueen, L. A., Sheehy, S. P. & Parker, K. K. Fibrous scaffolds for building hearts and heart parts. Adv. Drug Deliv. Rev. 96, 83–102 (2016).

    CAS  PubMed  Google Scholar 

  41. Mauck, R. L. et al. Engineering on the straight and narrow: the mechanics of nanofibrous assemblies for fiber-reinforced tissue regeneration. Tissue Eng. Part B 15, 171–193 (2009).

    CAS  Google Scholar 

  42. Pope, A. J., Sands, G. B., Smaill, B. H. & LeGrice, I. J. Three-dimensional transmural organization of perimysial collagen in the heart. Am. J. Physiol. Heart C 295, 1243–1252 (2008).

    Google Scholar 

  43. Sheehy, S. P., Grosberg, A. & Parker, K. K. The contribution of cellular mechanotransduction to cardiomyocyte form and function. Biomech. Model. Mechanobiol. 11, 1227–1239 (2012).

    PubMed  PubMed Central  Google Scholar 

  44. Kim, D. H. et al. Nanoscale cues regulate the structure and function of macroscopic cardiac tissue constructs. Proc. Natl Acad. Sci. USA 107, 565–570 (2010).

    CAS  PubMed  Google Scholar 

  45. Savadjiev, P. et al. Heart wall myofibers are arranged in minimal surfaces to optimize organ function. Proc. Natl Acad. Sci. USA 109, 9248–9253 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Deravi, L. F. et al. Design and fabrication of fibrous nanomaterials using pull spinning. Macromol. Mater. Eng. 302, 1600404 (2017).

    Google Scholar 

  47. Ruoslahti, E. RGD and other recognition sequences for integrins. Annu Rev. Cell Dev. Biol. 12, 697–715 (1996).

    CAS  PubMed  Google Scholar 

  48. Katagiri, Y., Brew, S. A. & Ingham, K. C. All six modules of the gelatin-binding domain of fibronectin are required for full affinity. J. Biol. Chem. 278, 11897–11902 (2003).

    CAS  PubMed  Google Scholar 

  49. Meiry, G. et al. Evolution of action potential propagation and repolarization in cultured neonatal rat ventricular myocytes. J. Cardiovasc. Electrophysiol. 12, 1269–1277 (2001).

    CAS  PubMed  Google Scholar 

  50. Morse, P. M. & Feshbach, H. Methods of Theoretical Physics (McGraw-Hill, New York, 1953).

  51. Mandegar, M. A. et al. CRISPR interference efficiently induces specific and reversible gene silencing in human iPSCs. Cell Stem Cell 18, 541–553 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Rohr, S., Kucera, J. P. & Kleber, A. G. Slow conduction in cardiac tissue, I: effects of a reduction of excitability versus a reduction of electrical coupling on microconduction. Circ. Res 83, 781–794 (1998).

    CAS  PubMed  Google Scholar 

  53. Yang, X. L., Pabon, L. & Murry, C. E. Engineering adolescence maturation of human pluripotent stem cell-derived cardiomyocytes. Circ. Res. 114, 511–523 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Pasqualini, F. S., Sheehy, S. P., Agarwal, A., Aratyn-Schaus, Y. & Parker, K. K. Structural phenotyping of stem cell-derived cardiomyocytes. Stem Cell Rep. 4, 340–347 (2015).

    CAS  Google Scholar 

  55. Akselrod, S. et al. Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science 213, 220–222 (1981).

    CAS  PubMed  Google Scholar 

  56. Fenske, S. et al. Comprehensive multilevel in vivo and in vitro analysis of heart rate fluctuations in mice by ECG telemetry and electrophysiology. Nat. Protoc. 11, 61–86 (2016).

    CAS  PubMed  Google Scholar 

  57. Barrett, A. M. & Carter, J. Comparative chronotropic activity of beta-adrenoceptive antagonists. Br. J. Pharmacol. 40, 373–381 (1970).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Brito-Martins, M., Harding, S. E. & Ali, N. N. Beta(1)- and beta(2)-adrenoceptor responses in cardiomyocytes derived from human embryonic stem cells: comparison with failing and non-failing adult human heart. Br. J. Pharmacol. 153, 751–759 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Simpson, P. & Savion, S. Differentiation of rat myocytes in single cell cultures with and without proliferating nonmyocardial cells. Cross-striations, ultrastructure, and chronotropic response to isoproterenol. Circ. Res. 50, 101–116 (1982).

    CAS  PubMed  Google Scholar 

  60. Moretti, A. et al. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N. Engl. J. Med. 363, 1397–1409 (2010).

    CAS  PubMed  Google Scholar 

  61. Koglin, J., Bohm, M., Vonscheidt, W., Stablein, A. & Erdmann, E. Antiadrenergic effect of carbachol but not of adenosine on contractility in the intact human ventricle in-vivo. J. Am. Coll. Cardiol. 23, 678–683 (1994).

    CAS  PubMed  Google Scholar 

  62. Lim, Z. Y., Maskara, B., Aguel, F., Emokpae, R.Jr & Tung, L. Spiral wave attachment to millimeter-sized obstacles. Circulation 114, 2113–2121 (2006).

    PubMed  Google Scholar 

  63. Ogle, B. M. et al. Distilling complexity to advance cardiac tissue engineering. Sci. Transl. Med. 8, 342ps313 (2016).

    Google Scholar 

  64. Feinberg, A. W. et al. Muscular thin films for building actuators and powering devices. Science 317, 1366–1370 (2007).

    CAS  PubMed  Google Scholar 

  65. Novosel, E. C., Kleinhans, C. & Kluger, P. J. Vascularization is the key challenge in tissue engineering. Adv. Drug Deliv. Rev. 63, 300–311 (2011).

    CAS  PubMed  Google Scholar 

  66. Lundberg, M. S., Baldwin, J. T. & Buxton, D. B. Building a bioartificial heart: obstacles and opportunities. J. Thorac. Cardiovasc. Surg. 153, 748–750 (2017).

    PubMed  Google Scholar 

  67. Chaturvedi, R. R. et al. Passive stiffness of myocardium from congenital heart disease and implications for diastole. Circulation 121, 979–988 (2010).

    PubMed  Google Scholar 

  68. Quinn, K. P. et al. Optical metrics of the extracellular matrix predict compositional and mechanical changes after myocardial infarction. Sci. Rep. 6, 35823 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Gonzalez, G. M. et al. Production of synthetic, para-aramid and biopolymer nanofibers by immersion rotary jet-spinning. Macromol. Mater. Eng. 302, 1600365 (2017).

    Google Scholar 

  70. Gladman, A. S., Matsumoto, E. A., Nuzzo, R. G., Mahadevan, L. & Lewis, J. A. Biomimetic 4D printing. Nat. Mater. 15, 413–418 (2016).

    PubMed  Google Scholar 

  71. Zimmermann, W. H. et al. Three-dimensional engineered heart tissue from neonatal rat cardiac myocytes. Biotechnol. Bioeng. 68, 106–114 (2000).

    CAS  PubMed  Google Scholar 

  72. Germanguz, I. et al. Molecular characterization and functional properties of cardiomyocytes derived from human inducible pluripotent stem cells. J. Cell Mol. Med. 15, 38–51 (2011).

    CAS  PubMed  Google Scholar 

  73. Ronaldson-Bouchard, K. et al. Advanced maturation of human cardiac tissue grown from pluripotent stem cells. Nature 556, 239–243 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Endoh, M. Force–frequency relationship in intact mammalian ventricular myocardium: physiological and pathophysiological relevance. Eur. J. Pharmacol. 500, 73–86 (2004).

    CAS  PubMed  Google Scholar 

  75. Bai, S. L., Campbell, S. E., Moore, J. A., Morales, M. C. & Gerdes, A. M. Influence of age, growth, and sex on cardiac myocyte size and number in rats. Anat. Rec. 226, 207–212 (1990).

    CAS  PubMed  Google Scholar 

  76. Feric, N. T. & Radisic, M. Strategies and challenges to myocardial replacement therapy. Stem Cells Transl. Med. 5, 410–416 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Pecha, S., Eschenhagen, T. & Reichenspurner, H. Myocardial tissue engineering for cardiac repair. J. Heart Lung Transplant. 35, 294–298 (2016).

    PubMed  Google Scholar 

  78. Klabunde, R. E. Cardiovascular Physiology Concepts 2nd edn (Lippincott Williams & Wilkins/Wolters Kluwer, Philadelphia, 2012).

  79. Park, S. J. et al. Phototactic guidance of a tissue-engineered soft-robotic ray. Science 353, 158–162 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Guyette, J. P. et al. Bioengineering human myocardium on native extracellular matrix. Circ. Res. 118, 56–72 (2016).

    CAS  PubMed  Google Scholar 

  81. Laughner, J. I., Ng, F. S., Sulkin, M. S., Arthur, R. M. & Efimov, I. R. Processing and analysis of cardiac optical mapping data obtained with potentiometric dyes. Am. J. Physiol. Heart C 303, H753–H765 (2012).

    CAS  Google Scholar 

  82. Pearce, J. A., Porterfield, J. E., Larson, E. R., Valvano, J. W. & Feldman, M. D. Accuracy considerations in catheter based estimation of left ventricular volume. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2010, 3556–3558 (2010).

    Google Scholar 

  83. Baan, J. et al. Continuous stroke volume and cardiac output from intra-ventricular dimensions obtained with impedance catheter. Cardiovasc. Res. 15, 328–334 (1981).

    CAS  PubMed  Google Scholar 

  84. Baan, J. et al. Continuous measurement of left ventricular volume in animals and humans by conductance catheter. Circulation 70, 812–823 (1984).

    CAS  PubMed  Google Scholar 

  85. Raghavan, K. et al. Electrical conductivity and permittivity of murine myocardium. IEEE Trans. Biomed. Eng. 56, 2044–2053 (2009).

    PubMed  Google Scholar 

  86. Clark, J. E. & Marber, M. S. Advancements in pressure–volume catheter technology—stress remodelling after infarction. Exp. Physiol. 98, 614–621 (2013).

    PubMed  Google Scholar 

Download references

Acknowledgements

This work was sponsored by the John A. Paulson School of Engineering and Applied Sciences at Harvard University, the Wyss Institute for Biologically Inspired Engineering at Harvard University, Harvard Materials Research Science and Engineering Center grant DMR-1420570, Defense Threat Reduction Agency (DTRA) subcontract #312659 from Los Alamos National Laboratory under a prime DTRA contract no. DE-AC52-06NA25396, and the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Numbers UH3TR000522 and 1-UG3-HL-141798-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was supported in part by the US Army Research Laboratory and the US Army Research Office under Contract No. W911NF-12-2-0036. The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the Army Research Office, Army Research Laboratory, or the US government. The US government is authorized to reproduce and distribute reprints for government purposes notwithstanding any copyright notation hereon. This work was performed in part at the Center for Nanoscale Systems (CNS), a member of the National Nanotechnology Coordinated Infrastructure Network (NNCI), which is supported by the National Science Foundation under NSF award no. 1541959. CNS is part of Harvard University. We thank M. McKenna and the staff at Harvard University’s John A. Paulson School of Engineering and Applied Sciences Scientific Instrument Shop for manufacturing heart bioreactor and nanofibre production system components. We thank M. Griswold and A. Cho for technical assistance, J. Guyette and H. Ott for providing decellularized human left ventricle myocardial tissue samples, E. Snay for assistance with echocardiographic imaging at the Boston Children’s Hospital Small Animal Imaging Laboratory, and M. Rosnach for assistance with photography and illustrations. We thank A. Kleber for his expertise and insightful discussions.

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Authors and Affiliations

  1. Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA

    Luke A. MacQueen, Sean P. Sheehy, Christophe O. Chantre, John F. Zimmerman, Francesco S. Pasqualini, Josue A. Goss, Patrick H. Campbell, Grant M. Gonzalez, Sung-Jin Park, Andrew K. Capulli, John P. Ferrier, T. Fettah Kosar, L. Mahadevan & Kevin Kit Parker

  2. John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA

    Luke A. MacQueen, Sean P. Sheehy, Christophe O. Chantre, John F. Zimmerman, Francesco S. Pasqualini, Josue A. Goss, Patrick H. Campbell, Grant M. Gonzalez, Sung-Jin Park, Andrew K. Capulli, John P. Ferrier, L. Mahadevan & Kevin Kit Parker

  3. Department of Cardiology, Boston Children’s Hospital, Boston, MA, USA

    Xujie Liu & William T. Pu

  4. Kavli Institute for Bionano Science and Technology, Harvard University, Cambridge, MA, USA

    L. Mahadevan

  5. Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA

    L. Mahadevan

  6. Department of Physics, Harvard University, Cambridge, MA, USA

    L. Mahadevan

  7. Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA

    William T. Pu & Kevin Kit Parker

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Contributions

L.A.M. and K.K.P. conceived the ideas and designed the experiments. L.A.M., S.P.S., C.O.C., J.F.Z., F.S.P., X.L., J.A.G., P.H.C., G.M.G., S.-J.P., A.K.C., J.P.F. and T.F.K conducted the experiments and analysed the data. L.M. derived the scaling laws. L.A.M., W.T.P. and K.K.P interpreted the data. L.A.M., S.P.S. and K.K.P. wrote the manuscript.

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Correspondence to Kevin Kit Parker.

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Supplementary information

Supplementary Information

Supplementary figures and video captions.

Reporting Summary

Supplementary Video 1

Pull-spinning a nanofibrous ventricle scaffold.

Supplementary Video 2

Microcomputed-tomography reconstruction of a nanofibrous ventricle scaffold.

Supplementary Video 3

Spontaneous contraction of a plated neonatal rat ventricular myocyte tissue-engineered ventricle.

Supplementary Video 4

Magnified views of spontaneously contracting tissue-engineered ventricles.

Supplementary Video 5

Spontaneously contracting, sutured and catheterized neonatal rat ventricular myocyte tissue-engineered ventricle.

Supplementary Video 6

Calcium propagation on a neonatal rat ventricular myocyte tissue-engineered ventricle.

Supplementary Video 7

Calcium propagation on a human-induced-pluripotent-stem-cell-derived cardiomyocyte tissue-engineered ventricle surface.

Supplementary Video 8

Immunostained human-induced-pluripotent-stem-cell-derived cardiomyocytes in a polycaprolactone–gelatin nanofibre ventricle scaffold.

Supplementary Video 9

Heart bioreactor computer-aided-design drawings.

Supplementary Video 10

Echocardiographic imaging of a spontaneously beating neonatal rat ventricular myocyte tissue-engineered ventricle.

Supplementary Video 11

Echocardiographic imaging of a ventricle scaffold for which contraction was driven by the heart bioreactor.

Supplementary Video 12

Calcium propagation on a neonatal-rat-ventricular-myocyte tissue-engineered ventricle before and after injury with a 1-mm-diameter biopsy punch.

Supplementary Video 13

Calcium propagation on a neonatal-rat-ventricular-myocyte tissue-engineered ventricle following injury with a 1-mm-diameter biopsy punch.

Supplementary Video 14

Contraction of neonatal-rat-ventricular-myocyte tissues following 40 days of culture in polycaprolactone–gelatin nanofibrous sheets.

Supplementary Video 15

Membrane staining of neonatal-rat-ventricular-myocyte tissues following 45 days of culture in polycaprolactone–gelatin nanofibrous sheets.

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MacQueen, L.A., Sheehy, S.P., Chantre, C.O. et al. A tissue-engineered scale model of the heart ventricle. Nat Biomed Eng 2, 930–941 (2018). https://doi.org/10.1038/s41551-018-0271-5

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  • DOI: https://doi.org/10.1038/s41551-018-0271-5

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