The Intrinsic Fatigue Mechanism of the Porcine Aortic Valve Extracellular Matrix

  • Jun Liao
  • Erinn M. Joyce
  • W. David Merryman
  • Hugh L. Jones
  • Mina Tahai
  • M. F. Horstemeyer
  • Lakiesha N. Williams
  • Richard A. Hopkins
  • Michael S. Sacks
Article

Abstract

Decellularized aortic valves (AV) are promising scaffolds for tissue engineered heart valve (TEHV) application; however, it is not known what the intrinsic fatigue mechanism of the AV extracellular matrix (ECM) is and how this relates to decellularized AV functional limits when tissue remodeling does not take place. In this study, decellularized AVs were subjected to in vitro cardiac exercising and the exercised leaflets were characterized to assess the structural and mechanical alterations. A flow-loop cardiac exerciser was designed to allow for pulsatile flow conditions while maintaining sterility. The acellular valve conduits were sutured into a silicone root with the Valsalva sinus design and subjected to cardiac cycling for 2 weeks (1.0 million cycles) and 4 weeks (2.0 million cycles). Following exercising, thorough structural and mechanical characterizations were then performed. The overall morphology was maintained and the exercised leaflets were able to coapt and support load; however, the leaflets exhibited an unfolded and thinned morphology. The straightening of the locally wavy collagen fiber structure was confirmed by histology and small angle light scattering; the disruption of elastin network was also observed. Biaxial mechanical testing showed that the leaflet extensibility was largely reduced by cardiac exercising. In the absence of cellular maintenance, decellularized leaflets experience structural fatigue due to lack of exogenous stabilizing crosslinks, and the structural disruption is irreversible and cumulative. Although not being a means to predict the durability of the acellular valve implants, this mechanistic study reveals the fatigue pattern of the acellular leaflets and implies the importance of recellularization in developing a TEHV, in which long term durability will likely be better achieved by continual remodeling and repair of the valvular ECM.

Keywords

Aortic valve leaflet Extracellular matrix Decellularization Cyclic fatigue Tissue engineering 

References

  1. 1.
    Angell, W. W., J. H. Oury, C. G. Duran, and C. Infantes-Alcon. Twenty-year comparison of the human allograft and porcine xenograft. Ann. Thorac. Surg. 48(3 Suppl):S89–S90, 1989.CrossRefGoogle Scholar
  2. 2.
    Bader, A., T. Schilling, O. E. Teebken, G. Brandes, T. Herden, G. Steinhoff, et al. Tissue engineering of heart valves—human endothelial cell seeding of detergent acellularized porcine valves. Eur. J. Cardiothorac. Surg. 14(3):279–284, 1998.CrossRefGoogle Scholar
  3. 3.
    Bertipaglia, B., F. Ortolani, L. Petrelli, G. Gerosa, M. Spina, P. Pauletto, et al. Cell characterization of porcine aortic valve and decellularized leaflets repopulated with aortic valve interstitial cells: the VESALIO Project (Vitalitate Exornatum Succedaneum Aorticum Labore Ingenioso Obtenibitur). Ann. Thorac. Surg. 75(4):1274–1282, 2003.CrossRefGoogle Scholar
  4. 4.
    Booth, C., S. A. Korossis, H. E. Wilcox, K. G. Watterson, J. N. Kearney, J. Fisher, et al. Tissue engineering of cardiac valve prostheses I: development and histological characterization of an acellular porcine scaffold. J. Heart Valve Dis. 11(4):457–462, 2002.Google Scholar
  5. 5.
    Cannegieter, S., F. Rosendaal, and E. Briet. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation 89:635–641, 1994.Google Scholar
  6. 6.
    Cebotari, S., H. Mertsching, K. Kallenbach, S. Kostin, O. Repin, A. Batrinac, et al. Construction of autologous human heart valves based on an acellular allograft matrix. Circulation 106(12 Suppl 1):I63–I68, 2002.Google Scholar
  7. 7.
    Courtman, D. W., C. A. Pereira, S. Omar, S. E. Langdon, J. M. Lee, and G. J. Wilson. Biomechanical and ultrastructural comparison of cryopreservation and a novel cellular extraction of porcine aortic valve leaflets. J. Biomed. Mater. Res. 29(12):1507–1516, 1995.CrossRefGoogle Scholar
  8. 8.
    da Costa, F. D., A. C. Costa, R. Prestes, A. C. Domanski, E. M. Balbi, A. D. Ferreira, et al. The early and midterm function of decellularized aortic valve allografts. Ann. Thorac. Surg. 90(6):1854–1860, 2010. doi:S0003-4975(10)01872-2[pii]10.1016/j.athoracsur.2010.08.022.CrossRefGoogle Scholar
  9. 9.
    Fung, Y. C. Biomechanics: Mechanical Properties of Living Tissues. New York: Springer, 1981.Google Scholar
  10. 10.
    Gloeckner, D. C., K. L. Billiar, and M. S. Sacks. Effects of mechanical fatigue on the bending properties of the porcine bioprosthetic heart valve. ASAIO J. 45(1):59–63, 1999.CrossRefGoogle Scholar
  11. 11.
    Grabow, N., K. Schmohl, A. Khosravi, M. Philipp, M. Scharfschwerdt, B. Graf, et al. Mechanical and structural properties of a novel hybrid heart valve scaffold for tissue engineering. Artif. Organs. 28(11):971–979, 2004.CrossRefGoogle Scholar
  12. 12.
    Hammermeister, K., G. K. Sethi, W. G. Henderson, F. L. Grover, C. Oprian, and S. H. Rahimtoola. Outcomes 15 years after valve replacement with a mechanical versus a bioprosthetic valve: final report of the Veterans Affairs randomized trial. J. Am. Coll. Cardiol. 36(4):1152–1158, 2000.CrossRefGoogle Scholar
  13. 13.
    Hoerstrup, S. P., R. Sodian, S. Daebritz, J. Wang, E. A. Bacha, D. P. Martin, et al. Functional living trileaflet heart valves grown in vitro. Circulation 102(19 Suppl 3):III44–III49, 2000.Google Scholar
  14. 14.
    Joyce, E. M., J. Liao, F. J. Schoen, J. E. Mayer, Jr., and M. S. Sacks. Functional collagen fiber architecture of the pulmonary heart valve cusp. Ann. Thorac. Surg. 87(4):1240–1249, 2009. doi:S0003-4975(08)02694-5[pii]10.1016/j.athoracsur.2008.12.049..CrossRefGoogle Scholar
  15. 15.
    Korossis, S. A., C. Booth, H. E. Wilcox, K. G. Watterson, J. N. Kearney, J. Fisher, et al. Tissue engineering of cardiac valve prostheses II: biomechanical characterization of decellularized porcine aortic heart valves. J. Heart Valve Dis. 11(4):463–471, 2002.Google Scholar
  16. 16.
    Lee, T. C., R. J. Midura, V. C. Hascall, and I. Vesely. The effect of elastin damage on the mechanics of the aortic valve. J. Biomech. 34(2):203–210, 2001. doi:S0021-9290(00)00187-1[pii].CrossRefGoogle Scholar
  17. 17.
    Liao, J., E. M. Joyce, and M. S. Sacks. Effects of decellularization on mechanical and structural properties of the porcine aortic valve leaflets. Biomaterials 29(8):1065–1074, 2008.CrossRefGoogle Scholar
  18. 18.
    Liao, J., L. Yang, J. Grashow, and M. S. Sacks. Molecular orientation of collagen in intact planar connective tissues under biaxial stretch. Acta Biomater. 1(1):45–54, 2005.CrossRefGoogle Scholar
  19. 19.
    Liao, J., L. Yang, J. Grashow, and M. S. Sacks. The relation between collagen fibril kinematics and mechanical properties in the mitral valve anterior leaflet. J. Biomech. Eng. 129(1):78–87, 2007.CrossRefGoogle Scholar
  20. 20.
    Lovekamp, J. J., D. T. Simionescu, J. J. Mercuri, B. Zubiate, M. S. Sacks, and N. R. Vyavahare. Stability and function of glycosaminoglycans in porcine bioprosthetic heart valves. Biomaterials 27(8):1507–1518, 2006.CrossRefGoogle Scholar
  21. 21.
    Rabkin-Aikawa, E., M. Aikawa, M. Farber, J. R. Kratz, G. Garcia-Cardena, N. T. Kouchoukos, et al. Clinical pulmonary autograft valves: pathologic evidence of adaptive remodeling in the aortic site. J. Thorac. Cardiovasc. Surg. 128(4):552–561, 2004.CrossRefGoogle Scholar
  22. 22.
    Rajani, B., R. B. Mee, and N. B. Ratliff. Evidence for rejection of homograft cardiac valves in infants. J. Thorac. Cardiovasc. Surg. 115(1):111–117, 1998.CrossRefGoogle Scholar
  23. 23.
    Sacks, M. S., F. J. Schoen, and J. E. Mayer. Bioengineering challenges for heart valve tissue engineering. Annu. Rev. Biomed. Eng. 11:289–313, 2009. doi:10.1146/annurev-bioeng-061008-124903.CrossRefGoogle Scholar
  24. 24.
    Sacks, M. S., D. B. Smith, and E. D. Hiester. A small angle light scattering device for planar connective tissue microstructural analysis. Ann. Biomed. Eng. 25(4):678–689, 1997.CrossRefGoogle Scholar
  25. 25.
    Schoen, F. J. Pathology of heart valve substitution with mechanical and tissue prostheses. In: Cardiovascular Pathology, edited by M. D. Silver, A. I. Gotlieb, and F. J. Schoen. New York: Livingstone, 2001.Google Scholar
  26. 26.
    Schoen, F. J. Heart valve tissue engineering: quo vadis? Curr. Opin. Biotechnol. 2011. doi:S0958-1669(11)00018-8[pii]10.1016/j.copbio.2011.01.004.Google Scholar
  27. 27.
    Schoen, F., and R. Levy. Tissue heart valves: current challenges and future research perspectives. J. Biomed. Mater. Res. 47:439–465, 1999.CrossRefGoogle Scholar
  28. 28.
    Schoen, F., R. Levy, and H. Piehler. Pathological considerations in replacement cardiac valves. Cardiovasc. Pathol. 1(1):29–52, 1992.CrossRefGoogle Scholar
  29. 29.
    Senthilnathan, V., T. Treasure, G. Grunkemeier, and A. Starr. Heart valves: which is the best choice? Cardiovasc. Surg. 7(4):393–397, 1999.CrossRefGoogle Scholar
  30. 30.
    Shinoka, T., C. K. Breuer, R. E. Tanel, G. Zund, T. Miura, P. X. Ma, et al. Tissue engineering heart valves: valve leaflet replacement study in a lamb model. Ann. Thorac. Surg. 60(6 Suppl):S513–S516, 1995.CrossRefGoogle Scholar
  31. 31.
    Sodian, R., S. P. Hoerstrup, J. S. Sperling, S. Daebritz, D. P. Martin, A. M. Moran, 19 Suppl 3, et al. Early In vivo experience with tissue-engineered trileaflet heart valves. Circulation 102(19 Suppl 3):III22–III29, 2000.Google Scholar
  32. 32.
    Spina, M., F. Ortolani, A. E. Messlemani, A. Gandaglia, J. Bujan, N. Garcia-Honduvilla, et al. Isolation of intact aortic valve scaffolds for heart-valve bioprostheses: extracellular matrix structure, prevention from calcification, and cell repopulation features. J. Biomed. Mater. Res. A. 67(4):1338–1350, 2003.CrossRefGoogle Scholar
  33. 33.
    Stamm, C., A. Khosravi, N. Grabow, K. Schmohl, N. Treckmann, A. Drechsel, et al. Biomatrix/polymer composite material for heart valve tissue engineering. Ann. Thorac. Surg. 78(6):2084–2093, 2004.CrossRefGoogle Scholar
  34. 34.
    Steinhoff, G., U. Stock, N. Karim, H. Mertsching, A. Timke, R. R. Meliss, et al. Tissue engineering of pulmonary heart valves on allogenic acellular matrix conduits: in vivo restoration of valve tissue. Circulation 102(19 Suppl 3):III50–III55, 2000.Google Scholar
  35. 35.
    Stock, U. A., M. Nagashima, P. N. Khalil, G. D. Nollert, T. Herden, J. S. Sperling, et al. Tissue-engineered valved conduits in the pulmonary circulation. J. Thorac. Cardiovasc. Surg. 119(4 Pt 1):732–740, 2000.CrossRefGoogle Scholar
  36. 36.
    Stock, U. A., J. P. Vacanti, J. E. Mayer, Jr., and T. Wahlers. Tissue engineering of heart valves—current aspects. Thorac. Cardiovasc. Surg. 50(3):184–193, 2002.CrossRefGoogle Scholar
  37. 37.
    Thubrikar, M. The Aortic Valve. Boca Raton: CRC, 1990.Google Scholar
  38. 38.
    Vesely, I. Heart valve tissue engineering. Circ. Res. 97:743–755, 2005.CrossRefGoogle Scholar
  39. 39.
    Wilson, G. J., D. W. Courtman, P. Klement, J. M. Lee, and H. Yeger. Acellular matrix: a biomaterials approach for coronary artery bypass and heart valve replacement. Ann. Thorac. Surg. 60(2 Suppl):S353–S358, 1995.CrossRefGoogle Scholar
  40. 40.
    Wilson, G. J., H. Yeger, P. Klement, J. M. Lee, and D. W. Courtman. Acellular matrix allograft small caliber vascular prostheses. ASAIO Trans. 36(3):M340–M343, 1990.Google Scholar
  41. 41.
    Yacoub, M., N. R. Rasmi, T. M. Sundt, O. Lund, E. Boyland, R. Radley-Smith, et al. Fourteen-year experience with homovital homografts for aortic valve replacement. J. Thorac. Cardiovasc. Surg. 110(1):186–193, 1995; (discussion 93-4).CrossRefGoogle Scholar
  42. 42.
    Yacoub, M. H., and J. J. Takkenberg. Will heart valve tissue engineering change the world? Nat. Clin. Pract. Cardiovasc. Med. 2(2):60–61, 2005. doi:ncpcardio0112[pii]10.1038/ncpcardio0112.CrossRefGoogle Scholar
  43. 43.
    Yannas, I. Natural Materials. Biomaterial Science. San Diego: Academic Press, 1996.Google Scholar
  44. 44.
    Zeltinger, J., L. K. Landeen, H. G. Alexander, I. D. Kidd, and B. Sibanda. Development and characterization of tissue-engineered aortic valves. Tissue Eng. 7(1):9–22, 2001.CrossRefGoogle Scholar

Copyright information

© Biomedical Engineering Society 2012

Authors and Affiliations

  • Jun Liao
    • 1
  • Erinn M. Joyce
    • 2
  • W. David Merryman
    • 3
  • Hugh L. Jones
    • 1
  • Mina Tahai
    • 1
  • M. F. Horstemeyer
    • 1
  • Lakiesha N. Williams
    • 1
  • Richard A. Hopkins
    • 4
  • Michael S. Sacks
    • 2
  1. 1.Tissue Bioengineering Laboratory, Department of Agricultural and Biological Engineering, Computational Manufacturing and Design, CAVSMississippi State UniversityMississippi StateUSA
  2. 2.Department of Bioengineering and McGowan Institute for Regenerative MedicineCardiovascular Biomechanics Laboratory, University of PittsburghPittsburghUSA
  3. 3.Department of Biomedical EngineeringVanderbilt UniversityNashvilleUSA
  4. 4.Department of Cardiac SurgeryChildrens’s Mercy Hospital and ClinicsKansas CityUSA

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