Abstract
Current pediatric heart valve replacement options are suboptimal because they are incapable of somatic growth. Thus, children typically have multiple surgeries to replace outgrown valves. In this study, we present the in vivo function and growth potential of our tissue-engineered pediatric tubular valve. The valves were fabricated by sewing two decellularized engineered tissue tubes together in a prescribed pattern using degradable sutures and subsequently implanted into the main pulmonary artery of growing lambs. Valve function was monitored using periodic ultrasounds after implantation throughout the duration of the study. The valves functioned well up to 8 weeks, 4 weeks beyond the suture strength half-life, after which their insufficiency index worsened. Histology from the explanted valves revealed extensive host cell invasion within the engineered root and commencing from the leaflet surfaces. These cells expressed multiple phenotypes, including endothelial, and deposited elastin and collagen IV. Although the tubes fused together along the degradable suture line as designed, the leaflets shortened compared to their original height. This shortening is hypothesized to result from inadequate fusion at the commissures prior to suture degradation. With appropriate commissure reinforcement, this novel heart valve may provide the somatic growth potential desired for a pediatric valve replacement.
Similar content being viewed by others
References
Akay, H. O., C. A. Ozmen, A. H. Bayrak, S. Senturk, S. Katar, H. Nazaroglu, and M. Taskesen. Diameters of normal thoracic vascular structures in pediatric patients. Surg. Radiol. Anat: SRA 31:801–807, 2009.
Cebotari, S., I. Tudorache, A. Ciubotaru, D. Boethig, S. Sarikouch, A. Goerler, A. Lichtenberg, E. Cheptanaru, S. Barnaciuc, A. Cazacu, O. Maliga, O. Repin, L. Maniuc, T. Breymann, and A. Haverich. Use of fresh decellularized allografts for pulmonary valve replacement may reduce the reoperation rate in children and young adults early report. Circulation 124:S115–S123, 2011.
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.
Delmo Walter, E. M., T. M. M. H. de By, R. Meyer, and R. Hetzer. The future of heart valve banking and of homografts: perspective from the Deutsches Herzzentrum Berlin. HSR Proc. Intensive Care Cardiovasc. Anesth. 4:97–108, 2012.
Driessen-Mol, A., M. Y. Emmert, P. E. Dijkman, L. Frese, B. Sanders, B. Weber, N. Cesarovic, M. Sidler, J. Leenders, R. Jenni, J. Grunenfelder, V. Falk, F. P. Baaijens, and S. P. Hoerstrup. Transcatheter implantation of homologous “off-the-shelf” tissue-engineered heart valves with self-repair capacity: long-term functionality and rapid in vivo remodeling in sheep. J. Am. Coll. Cardiol. 63:1320–1329, 2014.
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. Part A 15:2965–2976, 2009.
Gottlieb, D., B. Fata, A. J. Powell, C. A. Cois, D. Annese, K. Tandon, G. Stetten, J. E. Mayer, Jr, and M. S. Sacks. Pulmonary artery conduit in vivo dimensional requirements in a growing ovine model: comparisons with the ascending aorta. J. Heart Valve Dis. 22:195–203, 2013.
Gottlieb, D., T. Kunal, S. Emani, E. Aikawa, D. W. Brown, A. J. Powell, A. Nedder, G. C. Engelmayr, Jr, J. M. Melero-Martin, M. S. Sacks, and J. E. Mayer, Jr. In vivo monitoring of function of autologous engineered pulmonary valve. J. Thorac. Cardiovasc. Surg. 139:723–731, 2010.
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. Functional living trileaflet heart valves grown in vitro. Circulation 102:III44–II49, 2000.
Jacobs, J. P., C. Mavroudis, J. A. Quintessenza, P. J. Chai, S. K. Pasquali, K. D. Hill, L. A. Vricella, M. L. Jacobs, J. A. Dearani, and D. Cameron. Reoperations for pediatric and congenital heart disease: an analysis of the Society of Thoracic Surgeons (STS) congenital heart surgery database. Semin. Thorac. Cardiovasc. Surg. Pediatr. Cardiac Surg. Annu. 17:2–8, 2014.
Kheradvar, A., E. M. Groves, L. P. Dasi, S. H. Alavi, R. Tranquillo, K. J. Grande-Allen, C. A. Simmons, B. Griffith, A. Falahatpisheh, C. J. Goergen, M. R. Mofrad, F. Baaijens, S. H. Little, and S. Canic. Emerging trends in heart valve engineering: Part I. Solutions for future. Ann. Biomed. Eng. 43:833–843, 2015.
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.
Maxon Monofilament Synthetic Absorbable Suture. 2008.
Mozaffarian, D., E. J. Benjamin, A. S. Go, D. K. Arnett, M. J. Blaha, M. Cushman, S. de Ferranti, J. P. Despres, H. J. Fullerton, V. J. Howard, M. D. Huffman, S. E. Judd, B. M. Kissela, D. T. Lackland, J. H. Lichtman, L. D. Lisabeth, S. Liu, R. H. Mackey, D. B. Matchar, D. K. McGuire, E. R. Mohler, 3rd, C. S. Moy, P. Muntner, M. E. Mussolino, K. Nasir, R. W. Neumar, G. Nichol, L. Palaniappan, D. K. Pandey, M. J. Reeves, C. J. Rodriguez, P. D. Sorlie, J. Stein, A. Towfighi, T. N. Turan, S. S. Virani, J. Z. Willey, D. Woo, R. W. Yeh, and M. B. Turner. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation 131:e29–322, 2015.
Protopapas, A. D., and T. Athanasiou. Contegra conduit for reconstruction of the right ventricular outflow tract: a review of published early and mid-time results. J. Cardiothorac. Surg. 3:62, 2008.
Quality A. f. H. R. A. Healthcare Cost and Utilization Project (HCUP). 2014.
Raymond, T. E., J. E. Khabbaza, R. Yadav, and A. R. Tonelli. Significance of main pulmonary artery dilation on imaging studies. Ann. Am. Thorac. Soc. 11:1623–1632, 2014.
Reimer, J. M., Z. H. Syedain, B. H. Haynie, and R. T. Tranquillo. Pediatric tubular pulmonary heart valve from decellularized engineered tissue tubes. Biomaterials 62:88–94, 2015.
Ruzmetov, M., J. J. Shah, D. M. Geiss, and R. S. Fortuna. Decellularized versus standard cryopreserved valve allografts for right ventricular outflow tract reconstruction: a single-institution comparison. J. Thorac. Cardiovasc. Surg. 143:543–549, 2012.
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. T. Baaijens, and S. P. Hoerstrup. Minimally-invasive implantation of living tissue engineered heart valves. J. Am. Coll. Cardiol. 56:510–520, 2010.
Starcher, B. C., and M. J. Galione. Purification and comparison of elastins from different animal species. Anal. Biochem. 74:441–447, 1976.
Stegemann, H., and K. Stalder. Determination of hydroxyproline. Clin. Chim. Acta 18:267–273, 1967.
Syedain, Z. H., M. T. Lahti, S. L. Johnson, P. S. Robinson, G. R. Ruth, R. W. Bianco, and R. T. 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.
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.
Syedain, Z. H., L. A. Meier, J. M. Reimer, and R. T. Tranquillo. Tubular heart valves from decellularized engineered tissue. Ann. Biomed. Eng. 41:2645–2654, 2013.
Syedain Z., J. Reimer, M. Lahti, J. Berry, R. Bianco and R. Tranquillo. 50-week implant of a tissue-engineered pulmonary conduit in a growing lamb model. In: 2015 4th TERMIS World Congress. Boston, MA: Tissue Engineering Part A, 2015, p. s-82.
Syedain, Z., J. Reimer, J. Schmidt, M. Lahti, J. Berry, R. Bianco, and R. T. Tranquillo. 6-Month aortic valve implantation of an off-the-shelf tissue-engineered valve in sheep. Biomaterials 73:175–184, 2015.
Tudorache, I., S. Cebotari, G. Sturz, L. Kirsch, C. Hurschler, A. Hilfiker, A. Haverich, and A. Lichtenberg. Tissue engineering of heart valves: biomechanical and morphological properties of decellularized heart valves. J. Heart Valve Dis. 16:567–573, 2007.
Weber, M., E. Heta, R. Moreira, V. N. Gesche, T. Schermer, J. Frese, S. Jockenhoevel, and P. Mela. Tissue-engineered fibrin-based heart valve with a tubular leaflet design. Tissue Eng. Part C Methods 20:265–275, 2014.
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.
Zubairi, R., S. Malik, R. D. Jaquiss, M. Imamura, J. Gossett, and W. R. Morrow. Risk factors for prosthesis failure in pulmonary valve replacement. Ann. Thorac. Surg. 91:561–565, 2011.
Acknowledgments
The authors acknowledge technical assistance from Sandy Johnson, Naomi Ferguson, Susan Saunders, the UMN Medical Devices Center, and the staff of the UMN Experimental Surgical Services and funding from NIH R01 HL107572 to R.T.T.
Author information
Authors and Affiliations
Corresponding author
Additional information
Associate Editor Lakshmi Prasad Dasi oversaw the review of this article.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Reimer, J., Syedain, Z., Haynie, B. et al. Implantation of a Tissue-Engineered Tubular Heart Valve in Growing Lambs. Ann Biomed Eng 45, 439–451 (2017). https://doi.org/10.1007/s10439-016-1605-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10439-016-1605-7