Technical Report | Published:

Perfusion-decellularized matrix: using nature's platform to engineer a bioartificial heart

Nature Medicine volume 14, pages 213221 (2008) | Download Citation

Abstract

About 3,000 individuals in the United States are awaiting a donor heart; worldwide, 22 million individuals are living with heart failure. A bioartificial heart is a theoretical alternative to transplantation or mechanical left ventricular support. Generating a bioartificial heart requires engineering of cardiac architecture, appropriate cellular constituents and pump function. We decellularized hearts by coronary perfusion with detergents, preserved the underlying extracellular matrix, and produced an acellular, perfusable vascular architecture, competent acellular valves and intact chamber geometry. To mimic cardiac cell composition, we reseeded these constructs with cardiac or endothelial cells. To establish function, we maintained eight constructs for up to 28 d by coronary perfusion in a bioreactor that simulated cardiac physiology. By day 4, we observed macroscopic contractions. By day 8, under physiological load and electrical stimulation, constructs could generate pump function (equivalent to about 2% of adult or 25% of 16-week fetal heart function) in a modified working heart preparation.

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References

  1. 1.

    & Immunosuppression for heart transplantation: where are we now? Nat. Clin. Pract. Cardiovasc. Med. 3, 203–212 (2006).

  2. 2.

    & Engineering myocardial tissue. Circ. Res. 97, 1220–1231 (2005).

  3. 3.

    et al. Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts. Nat. Med. 12, 452–458 (2006).

  4. 4.

    , , , & Cardiomyocyte bridging between hearts and bioengineered myocardial tissues with mesenchymal transition of mesothelial cells. J. Heart Lung Transplant. 25, 324–332 (2006).

  5. 5.

    et al. Extracellular matrix scaffold for cardiac repair. Circulation 112, I135–I143 (2005).

  6. 6.

    , , & Mathematical model of oxygen distribution in engineered cardiac tissue with parallel channel array perfused with culture medium containing oxygen carriers. Am. J. Physiol. Heart Circ. Physiol. 288, H1278–H1289 (2005).

  7. 7.

    et al. Pulsatile cardiac tissue grafts using a novel three-dimensional cell sheet manipulation technique functionally integrates with the host heart, in vivo. Circ. Res. 98, 705–712 (2006).

  8. 8.

    et al. Tissue cardiomyoplasty using bioengineered contractile cardiomyocyte sheets to repair damaged myocardium: their integration with recipient myocardium. Transplantation 80, 1586–1595 (2005).

  9. 9.

    , , , & A novel composite scaffold for cardiac tissue engineering. In Vitro Cell. Dev. Biol. Anim. 41, 188–196 (2005).

  10. 10.

    , , & Eleven years' experience with the Biocor stentless aortic bioprosthesis: clinical and hemodynamic follow-up with long-term relative survival rate. Eur. J. Cardiothorac. Surg. 22, 912–921 (2002).

  11. 11.

    et al. Decellularization protocols of porcine heart valves differ importantly in efficiency of cell removal and susceptibility of the matrix to recellularization with human vascular cells. J. Thorac. Cardiovasc. Surg. 127, 399–405 (2004).

  12. 12.

    et al. Recellularization of decellularized allograft scaffolds in ovine great vessel reconstructions. Ann. Thorac. Surg. 79, 888–896 (2005).

  13. 13.

    , , & Process development of an acellular dermal matrix (ADM) for biomedical applications. Biomaterials 25, 2679–2686 (2004).

  14. 14.

    , & Decellularization of tissues and organs. Biomaterials 27, 3675–3683 (2006).

  15. 15.

    et al. Biophysical regulation during cardiac development and application to tissue engineering. Int. J. Dev. Biol. 50, 233–243 (2006).

  16. 16.

    , & A simple method to renature DNA-binding proteins separated by SDS-polyacrylamide gel electrophoresis. Nucleic Acids Res. 21, 6040–6041 (1993).

  17. 17.

    et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 8, 241–254 (2005).

  18. 18.

    , , & Intracardiac pressures in the human fetus. Heart 84, 59–63 (2000).

  19. 19.

    , & Biomechanical properties of decellularized porcine common carotid arteries. Am. J. Physiol. Heart Circ. Physiol. 289, H1567–H1576 (2005).

  20. 20.

    et al. Development of a pericardial acellular matrix biomaterial: biochemical and mechanical effects of cell extraction. J. Biomed. Mater. Res. 28, 655–666 (1994).

  21. 21.

    et al. Development and characterization of an acellular human pericardial matrix for tissue engineering. Tissue Eng. 12, 763–773 (2006).

  22. 22.

    , , & Damage of porcine aortic valve tissue caused by the surfactant sodiumdodecylsulphate. Thorac. Cardiovasc. Surg. 34, 82–85 (1986).

  23. 23.

    et al. Mechanical and structural properties of a novel hybrid heart valve scaffold for tissue engineering. Artif. Organs 28, 971–979 (2004).

  24. 24.

    The Image Processing Handbook Ch 4. (CRC Press, London, 2002).

  25. 25.

    , , & in Numerical Recipies in C: The Art of Scientific Computing Ch. 12 (Cambridge University Press, Cambridge, UK, 1992).

  26. 26.

    & Improved technique of heart transplantation in rats. J. Thorac. Cardiovasc. Surg. 57, 225–229 (1969).

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Acknowledgements

We thank S. Keirstead and D. Lowe for access to electromechanical stimulation equipment and guidance; J. Sedgewick and J. Oja of the Biomedical Image Processing Laboratory at the University of Minnesota, Minneapolis, for access to photographic equipment and technical support; and the staff of the University of Minnesota CharFac facility, especially A. Ressler, for TEM assistance. This study was supported by a Faculty Research Development Grant to H.C.O. and D.A.T. from the Academic Health Center, University of Minnesota, Minneapolis, and by funding from the Center for Cardiovascular Repair, University of Minnesota, and the Medtronic Foundation to D.A.T.

Author information

Affiliations

  1. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.

    • Harald C Ott
  2. Center for Cardiovascular Repair, University of Minnesota, 312 Church Street Southeast, 7-105A NHH, Minneapolis, Minnesota 55455, USA.

    • Thomas S Matthiesen
    • , Saik-Kia Goh
    • , Stefan M Kren
    •  & Doris A Taylor
  3. Department of Biomedical Engineering, University of Minnesota, 312 Church Street Southeast, 7 NHH, Minneapolis, Minnesota 55455, USA.

    • Lauren D Black
    •  & Theoden I Netoff
  4. Department of Integrative Biology and Physiology, University of Minnesota, 6-125 Jackson Hall, 312 Church Street Southeast, Minneapolis, Minnesota 55455, USA.

    • Doris A Taylor

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Contributions

H.C.O. and D.A.T. conceived, designed and oversaw all of the studies, collection of results, interpretation of data and writing of the manuscript. H.C.O. was responsible for the primary undertaking, completion and supervision of all studies during his tenure at the University of Minnesota. T.S.M. designed and implemented the bioreactor studies along with H.C.O., participated in the mechanical testing studies and was instrumental in data and figure preparation for the final manuscript. S.-K.G. performed most of the immunohistochemistry and staining, except for the re-endothelialized tissues. L.D.B. performed the mechanical testing. S.M.K. decellularized the hearts, performed all surgeries and re-endothelialization experiments, and participated in the bioreactor studies. T.I.N. performed the motion analysis of the movies.

Corresponding author

Correspondence to Doris A Taylor.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figs. 1–3

Videos

  1. 1.

    Supplementary Movie 1

    Heterotopic transplant of decellularized rat heart into RNU rat abdomen.

  2. 2.

    Supplementary Movie 2

    Recellularization of decellularized heart tissue sections with neonatal cardiomyocytes.

  3. 3.

    Supplementary Movie 3

    Recellularized heart construct with an estimate of wall movement on day 4.

  4. 4.

    Supplementary Movie 4

    Recellularized heart construct with an estimate of wall movement on day 4.

About this article

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DOI

https://doi.org/10.1038/nm1684

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