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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Change history

  • 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.

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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.

Author information

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.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Kevin Kit Parker.

Supplementary information

  1. Supplementary Information

    Supplementary figures and video captions.

  2. Reporting Summary

  3. Supplementary Video 1

    Pull-spinning a nanofibrous ventricle scaffold.

  4. Supplementary Video 2

    Microcomputed-tomography reconstruction of a nanofibrous ventricle scaffold.

  5. Supplementary Video 3

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

  6. Supplementary Video 4

    Magnified views of spontaneously contracting tissue-engineered ventricles.

  7. Supplementary Video 5

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

  8. Supplementary Video 6

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

  9. Supplementary Video 7

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

  10. Supplementary Video 8

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

  11. Supplementary Video 9

    Heart bioreactor computer-aided-design drawings.

  12. Supplementary Video 10

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

  13. Supplementary Video 11

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

  14. 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.

  15. Supplementary Video 13

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

  16. Supplementary Video 14

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

  17. 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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DOI

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

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