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

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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Figure 1: Perfusion decellularization of whole rat hearts.
Figure 2: Composition and characteristics of decellularized rat heart tissue.
Figure 3: Vascular architecture of decellularized rat heart tissue.
Figure 4: Formation of a working perfused bioartificial heart-like construct by recellularization of decellularized cardiac ECM.
Figure 5: Histological analysis of recellularized rat heart constructs.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. Eschenhagen, T. & Zimmermann, W.H. Engineering myocardial tissue. Circ. Res. 97, 1220–1231 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Sekine, H., Shimizu, T., Kosaka, S., Kobayashi, E. & Okano, T. Cardiomyocyte bridging between hearts and bioengineered myocardial tissues with mesenchymal transition of mesothelial cells. J. Heart Lung Transplant. 25, 324–332 (2006).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  6. Radisic, M., Deen, W., Langer, R. & Vunjak-Novakovic, G. 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).

    Article  CAS  PubMed  Google Scholar 

  7. Furuta, A. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Park, H., Radisic, M., Lim, J.O., Chang, B.H. & Vunjak-Novakovic, G. A novel composite scaffold for cardiac tissue engineering. In Vitro Cell. Dev. Biol. Anim. 41, 188–196 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Dellgren, G., Eriksson, M.J., Brodin, L.A. & Radegran, K. 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).

    Article  PubMed  Google Scholar 

  11. Rieder, E. 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).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  13. Chen, R.N., Ho, H.O., Tsai, Y.T. & Sheu, M.T. Process development of an acellular dermal matrix (ADM) for biomedical applications. Biomaterials 25, 2679–2686 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Gilbert, T.W., Sellaro, T.L. & Badylak, S.F. Decellularization of tissues and organs. Biomaterials 27, 3675–3683 (2006).

    CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. Johnson, P., Maxwell, D.J., Tynan, M.J. & Allan, L.D. Intracardiac pressures in the human fetus. Heart 84, 59–63 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Roy, S., Silacci, P. & Stergiopulos, N. Biomechanical properties of decellularized porcine common carotid arteries. Am. J. Physiol. Heart Circ. Physiol. 289, H1567–H1576 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. Bodnar, E., Olsen, E.G., Florio, R. & Dobrin, J. Damage of porcine aortic valve tissue caused by the surfactant sodiumdodecylsulphate. Thorac. Cardiovasc. Surg. 34, 82–85 (1986).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Google Scholar 

  25. Press, W.H., Teukolsky, S.A., Vetterling, W.T. & Flannery, B.P. in Numerical Recipies in C: The Art of Scientific Computing Ch. 12 (Cambridge University Press, Cambridge, UK, 1992).

    Google Scholar 

  26. Ono, K. & Lindsey, E.S. Improved technique of heart transplantation in rats. J. Thorac. Cardiovasc. Surg. 57, 225–229 (1969).

    CAS  PubMed  Google Scholar 

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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.

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Authors and Affiliations

Authors

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

Supplementary Text and Figures

Supplementary Figs. 1–3 (PDF 1965 kb)

Supplementary Movie 1

Heterotopic transplant of decellularized rat heart into RNU rat abdomen. (MOV 1168 kb)

Supplementary Movie 2

Recellularization of decellularized heart tissue sections with neonatal cardiomyocytes. (MOV 544 kb)

Supplementary Movie 3

Recellularized heart construct with an estimate of wall movement on day 4. (MOV 816 kb)

Supplementary Movie 4

Recellularized heart construct with an estimate of wall movement on day 4. (MOV 1113 kb)

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Ott, H., Matthiesen, T., Goh, SK. et al. Perfusion-decellularized matrix: using nature's platform to engineer a bioartificial heart. Nat Med 14, 213–221 (2008). https://doi.org/10.1038/nm1684

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