Annals of Biomedical Engineering

, Volume 41, Issue 12, pp 2645–2654 | Cite as

Tubular Heart Valves from Decellularized Engineered Tissue

  • Zeeshan H. Syedain
  • Lee A. Meier
  • Jay M. Reimer
  • Robert T. Tranquillo


A novel tissue-engineered heart valve (TEHV) was fabricated from a decellularized tissue tube mounted on a frame with three struts, which upon back-pressure cause the tube to collapse into three coapting “leaflets.” The tissue was completely biological, fabricated from ovine fibroblasts dispersed within a fibrin gel, compacted into a circumferentially aligned tube on a mandrel, and matured using a bioreactor system that applied cyclic distension. Following decellularization, the resulting tissue possessed tensile mechanical properties, mechanical anisotropy, and collagen content that were comparable to native pulmonary valve leaflets. When mounted on a custom frame and tested within a pulse duplicator system, the tubular TEHV displayed excellent function under both aortic and pulmonary conditions, with minimal regurgitant fractions and transvalvular pressure gradients at peak systole, as well as well as effective orifice areas exceeding those of current commercially available valve replacements. Short-term fatigue testing of one million cycles with pulmonary pressure gradients was conducted without significant change in mechanical properties and no observable macroscopic tissue deterioration. This study presents an attractive potential alternative to current tissue valve replacements due to its avoidance of chemical fixation and utilization of a tissue conducive to recellularization by host cell infiltration.


Heart valve Tissue engineering Pulse duplicator Decellularization 



Authors will like to thank Naomi Ferguson, and Jillian Schmidt for technical assistance and Dave Hultman Design for machining the custom pulse duplicator system, bioreactor manifold and valve frames. The funding for the work was provided by NIH R01 HL107572 (to RTT).


  1. 1.
    Baaijens, F., C. Bouten, S. Hoerstrup, A. Mol, N. Driessen, and R. Boerboom. Functional tissue engineering of the aortic heart valve. Clin. Hemorheol. Microcirc. 33:197–199, 2005.PubMedGoogle Scholar
  2. 2.
    Christie, G. W. Anatomy of aortic heart valve leaflets: the influence of glutaraldehyde fixation on function. Eur. J. Cardiothorac. Surg. 6:S25–S32, 1992.CrossRefPubMedGoogle Scholar
  3. 3.
    Christie, G. W., and B. G. Barratt-Boyes. Mechanical properties of porcine pulmonary valve leaflets: how do they differ from aortic leaflets? Ann. Thorac. Surg. 60:S195–S199, 1995.CrossRefPubMedGoogle Scholar
  4. 4.
    Cox, J. L., N. Ad, K. Myers, M. Gharib, and R. C. Quijano. Tubular heart valves: a new tissue prosthesis design–preclinical evaluation of the 3F aortic bioprosthesis. J. Thorac. Cardiovasc. Surg. 130:520–527, 2005.CrossRefPubMedGoogle Scholar
  5. 5.
    Dahl, S. L., A. P. Kypson, J. H. Lawson, J. L. Blum, J. T. Strader, Y. Li, R. J. Manson, W. E. Tente, L. DiBernardo, M. T. Hensley, R. Carter, T. P. Williams, H. L. Prichard, M. S. Dey, K. G. Begelman, and L. E. Niklason. Readily available tissue-engineered vascular grafts. Sci. Transl. Med. 3:68ra69, 2011.CrossRefGoogle Scholar
  6. 6.
    Dijkman, P. E., A. Driessen-Mol, L. M. de Heer, J. Kluin, L. A. van Herwerden, B. Odermatt, F. P. Baaijens, and S. P. Hoerstrup. Trans-apical versus surgical implantation of autologous ovine tissue-engineered heart valves. J. Heart Valve Dis. 21:670–678, 2012.PubMedGoogle Scholar
  7. 7.
    Dijkman, P. E., A. Driessen-Mol, L. Frese, S. P. Hoerstrup, and F. P. Baaijens. Decellularized homologous tissue-engineered heart valves as off-the-shelf alternatives to xeno- and homografts. Biomaterials 33:4545–4554, 2012.CrossRefPubMedGoogle Scholar
  8. 8.
    Emmert, M. Y., B. Weber, L. Behr, T. Frauenfelder, C. E. Brokopp, J. Grunenfelder, V. Falk, and S. P. Hoerstrup. Transapical aortic implantation of autologous marrow stromal cell-based tissue-engineered heart valves: first experiences in the systemic circulation. JACC. Cardiovasc. Interv. 4:822–823, 2011.CrossRefPubMedGoogle Scholar
  9. 9.
    Flanagan, T. C., C. Cornelissen, S. Koch, B. Tschoeke, J. S. Sachweh, T. Schmitz-Rode, and S. Jockenhoevel. The in vitro development of autologous fibrin-based tissue-engineered heart valves through optimised dynamic conditioning. Biomaterials 28:3388–3397, 2007.CrossRefPubMedGoogle Scholar
  10. 10.
    Flanagan, T. C., J. S. Sachweh, J. Frese, H. Schnoring, N. Gronloh, S. Koch, R. H. Tolba, T. Schmitz-Rode, and S. Jockenhoevel. In vivo remodeling and structural characterization of fibrin-based tissue-engineered heart valves in the adult sheep model. Tissue Eng. A 15:2965–2976, 2009.CrossRefGoogle Scholar
  11. 11.
    Gerosa, G., V. Tarzia, G. Rizzoli, and T. Bottio. Small aortic annulus: the hydrodynamic performances of 5 commercially available tissue valves. J. Thorac. Cardiovasc. Surg. 131:1058–1064, 2006.CrossRefPubMedGoogle Scholar
  12. 12.
    Grassl, E. D., T. R. Oegema, and R. T. Tranquillo. A fibrin-based arterial media equivalent. J. Biomed. Mater. Res. A 66A:550–561, 2003.CrossRefGoogle Scholar
  13. 13.
    Hoerstrup, S. P., R. Sodian, S. Daebritz, J. Wang, E. A. Bacha, D. P. Martin, A. M. Moran, K. J. Guleserian, J. S. Sperling, S. Kaushal, J. P. Vacanti, F. J. Schoen, and J. E. Mayer Jr. Functional living trileaflet heart valves grown in vitro. Circulation 102:III44–III49, 2000.CrossRefPubMedGoogle Scholar
  14. 14.
    Isenberg, B. C., and R. T. Tranquillo. Long-term cyclic distention enhances the mechanical properties of collagen-based media-equivalents. Ann. Biomed. Eng. 31:937–949, 2003.CrossRefPubMedGoogle Scholar
  15. 15.
    Kim, Y. J., R. L. Sah, J. Y. Doong, and A. J. Grodzinsky. Fluorometric assay of DNA in cartilage explants using Hoechst 33258. Anal. Biochem. 174:168–176, 1988.CrossRefPubMedGoogle Scholar
  16. 16.
    Nakayama, Y., Y. Yahata, M. Yamanami, T. Tajikawa, K. Ohba, K. Kanda, and H. Yaku. A completely autologous valved conduit prepared in the open form of trileaflets (type VI biovalve): mold design and valve function in vitro. J. Biomed. Mater. Res. B Appl. Biomater. 99:135–141, 2011.PubMedGoogle Scholar
  17. 17.
    Neidert, M. R., and R. T. Tranquillo. Tissue-engineered valves with commissural alignment. Tissue Eng. 12:891–903, 2006.CrossRefPubMedGoogle Scholar
  18. 18.
    Quint, C., Y. Kondo, R. J. Manson, J. H. Lawson, A. Dardik, and L. E. Niklason. Decellularized tissue-engineered blood vessel as an arterial conduit. Proc. Natl. Acad. Sci. U. S. A. 108:9214–9219, 2011.CrossRefPubMedGoogle Scholar
  19. 19.
    Robinson, P. S., S. L. Johnson, M. C. Evans, V. H. Barocas, and R. T. Tranquillo. Functional tissue-engineered valves from cell-remodeled fibrin with commissural alignment of cell-produced collagen. Tissue Eng. A 14:83–95, 2008.CrossRefGoogle Scholar
  20. 20.
    Rouleau, L., D. Tremblay, R. Cartier, R. Mongrain, and R. L. Leask. Regional variations in canine descending aortic tissue mechanical properties change with formalin fixation. Cardiovasc. Pathol. 21:390–397, 2012.CrossRefPubMedGoogle Scholar
  21. 21.
    Schmidt, D., P. E. Dijkman, A. Driessen-Mol, R. Stenger, C. Mariani, A. Puolakka, M. Rissanen, T. Deichmann, B. Odermatt, B. Weber, M. Y. Emmert, G. Zund, F. P. Baaijens, and S. P. Hoerstrup. Minimally-invasive implantation of living tissue engineered heart valves: a comprehensive approach from autologous vascular cells to stem cells. J. Am. Coll. Cardiol. 56:510–520, 2010.CrossRefPubMedGoogle Scholar
  22. 22.
    Shinoka, T., C. K. Breuer, R. E. Tanel, G. Zund, T. Miura, P. X. Ma, R. Langer, J. P. Vacanti, and J. E. Mayer Jr. Tissue engineering heart valves: valve leaflet replacement study in a lamb model. Ann. Thorac. Surg. 60:S513–S516, 1995.CrossRefPubMedGoogle Scholar
  23. 23.
    Sodian, R., S. P. Hoerstrup, J. S. Sperling, S. Daebritz, D. P. Martin, A. M. Moran, B. S. Kim, F. J. Schoen, J. P. Vacanti, and J. E. Mayer Jr. Early in vivo experience with tissue-engineered trileaflet heart valves. Circulation 102:III22–III29, 2000.CrossRefPubMedGoogle Scholar
  24. 24.
    Stegemann, H., and K. Stalder. Determination of hydroxyproline. Clin. Chim. Acta 18:267–273, 1967.CrossRefPubMedGoogle Scholar
  25. 25.
    Stradins, P., R. Lacis, I. Ozolanta, B. Purina, V. Ose, L. Feldmane, and V. Kasyanov. Comparison of biomechanical and structural properties between human aortic and pulmonary valve. Eur. J. Cardiothorac. Surg. 26:634–639, 2004.CrossRefPubMedGoogle Scholar
  26. 26.
    Syedain, Z. H., A. R. Bradee, S. Kren, D. A. Taylor, and R. T. Tranquillo. Decellularized tissue-engineered heart valve leaflets with recellularization potential. Tissue Eng. A 19:759–769, 2013.CrossRefGoogle Scholar
  27. 27.
    Syedain, Z., M. T. Lahti, S. Johnson, P. Robinson, G. R. Ruth, R. Bianco, and R. Tranquillo. Implantation of a tissue engineered heart valve from human fibroblasts exhibiting short term function in the sheep pulmonary artery. Cardiovasc. Eng. Technol. 2:101–112, 2011.CrossRefGoogle Scholar
  28. 28.
    Syedain, Z. H., L. A. Meier, J. W. Bjork, A. Lee, and R. T. Tranquillo. Implantable arterial grafts from human fibroblasts and fibrin using a multi-graft pulsed flow-stretch bioreactor with noninvasive strength monitoring. Biomaterials 32:714–722, 2011.CrossRefPubMedGoogle Scholar
  29. 29.
    Syedain, Z. H., L. Meier, M. Lahti, S. Johnson, and R. T. Tranquillo. Implantation of completely biological, aligned engineered arteries pre-made from allogeneic fibroblasts in a sheep model. 2013 (submitted).Google Scholar
  30. 30.
    Syedain, Z. H., and R. T. Tranquillo. Controlled cyclic stretch bioreactor for tissue-engineered heart valves. Biomaterials 30:4078–4084, 2009.CrossRefPubMedGoogle Scholar
  31. 31.
    Syedain, Z. H., and R. T. Tranquillo. TGF-beta1 diminishes collagen production during long-term cyclic stretching of engineered connective tissue: implication of decreased ERK signaling. J. Biomech. 44:848–855, 2011.CrossRefPubMedGoogle Scholar
  32. 32.
    Syedain, Z. H., J. S. Weinberg, and R. T. Tranquillo. Cyclic distension of fibrin-based tissue constructs: evidence of adaptation during growth of engineered connective tissue. Proc. Natl. Acad. Sci. U. S. A. 105:6537–6542, 2008.CrossRefPubMedGoogle Scholar
  33. 33.
    Tower, T. T., M. R. Neidert, and R. T. Tranquillo. Fiber alignment imaging during mechanical testing of soft tissues. Ann. Biomed. Eng. 30:1221–1233, 2002.CrossRefPubMedGoogle Scholar
  34. 34.
    Weber, B., J. Scherman, M. Y. Emmert, J. Gruenenfelder, R. Verbeek, M. Bracher, M. Black, J. Kortsmit, T. Franz, R. Schoenauer, L. Baumgartner, C. Brokopp, I. Agarkova, P. Wolint, G. Zund, V. Falk, P. Zilla, and S. P. Hoerstrup. Injectable living marrow stromal cell-based autologous tissue engineered heart valves: first experiences with a one-step intervention in primates. Eur. Heart J. 32:2830–2840, 2011.CrossRefPubMedGoogle Scholar
  35. 35.
    Williams, C., S. L. Johnson, P. S. Robinson, and R. T. Tranquillo. Cell sourcing and culture conditions for fibrin-based valve constructs. Tissue Eng. 12:1489–1502, 2006.CrossRefPubMedGoogle Scholar

Copyright information

© Biomedical Engineering Society 2013

Authors and Affiliations

  • Zeeshan H. Syedain
    • 1
  • Lee A. Meier
    • 1
  • Jay M. Reimer
    • 1
  • Robert T. Tranquillo
    • 1
    • 2
  1. 1.Department of Biomedical EngineeringUniversity of MinnesotaMinneapolisUSA
  2. 2.Department of Chemical Engineering & Materials ScienceUniversity of MinnesotaMinneapolisUSA

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