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Comparing Scaffold Design and Recellularization Techniques for Development of Tissue Engineered Heart Valves

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Abstract

Valvular heart disease continues to afflict millions of people around the world. In many cases, the only corrective treatment for valvular heart disease is valve replacement. Valve replacement options are currently limited, and the most common constructs utilized are xenogenic tissue heart valves. The main limitation with the use of this valve type is the development of valve deterioration. Emerging evidence suggests that the underlying driver of valve deterioration is a chronic immune-mediated rejection process of the foreign xenogenic-derived tissue. There is an ongoing focus on the development of an immunologically acceptable, unfixed xenogeneic scaffold for future heart valve constructs. Tissue engineering heart valves are a promising method of develo** a durable, non-immunogenic, non-thrombotic, easily implantable, and readily available implant. In this review, we summarize the various decellularization protocols and scaffold designs for tissue engineered heart valve use and highlight the different cell types and methods for recellularization of tissue engineered heart valves.

Lay Summary

Valve replacement surgery is one of the most common procedures performed by cardiac surgeons. Most patients undergoing valve replacement surgery receive a tissue valve. Tissue valves are made from either cow or pig tissue, and unfortunately tend to fail over time requiring reoperation. One reason these valves fail may be due to a slow rejection of the animal tissue by the human immune system. There is an ongoing focus on the development of artificial heart valves using various tissue engineered designs. The purpose of this review is to summarize various designs and techniques for the creation of artificial heart valves.

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References

  1. Barone A, Benktander J, Teneberg S, Breimer ME. Characterization of acid and non-acid glycosphingolipids of porcine heart valve cusps as potential immune targets in biological heart valve grafts. Xenotransplantation. 2014;21:510–22. https://doi.org/10.1111/xen.12123.

    Article  Google Scholar 

  2. Griffiths LG, Choe LH, Reardon KF, Dow SW, Christopher OE. Immunoproteomic identification of bovine pericardium xenoantigens. Biomaterials. 2008;29:3514–20. https://doi.org/10.1016/j.biomaterials.2008.05.006.

    Article  CAS  Google Scholar 

  3. Gates KV, Dalgliesh AJ, Griffiths LG. Antigenicity of bovine pericardium determined by a novel immunoproteomic approach. Sci Rep. 2017;7:2446. https://doi.org/10.1038/s41598-017-02719-8.

    Article  CAS  Google Scholar 

  4. McGregor CGA, Carpentier A, Lila N, Logan JS, Byrne GW. Cardiac xenotransplantation technology provides materials for improved bioprosthetic heart valves. J Thorac Cardiovasc Surg. 2011;141:269–75. https://doi.org/10.1016/j.jtcvs.2010.08.064.

    Article  CAS  Google Scholar 

  5. Manji RA, Zhu LF, Nijjar NK, Rayner DC, Korbutt GS, Churchill TA, et al. Glutaraldehyde-fixed bioprosthetic heart valve conduits calcify and fail from xenograft rejection. Circulation. 2006;114:318–27. https://doi.org/10.1161/CIRCULATIONAHA.105.549311.

    Article  CAS  Google Scholar 

  6. Manji RA, Hara H, Cooper DKC. Characterization of the cellular infiltrate in bioprosthetic heart valves explanted from patients with structural valve deterioration. Xenotransplantation. 2015;22:406–7. https://doi.org/10.1111/xen.12187.

    Article  Google Scholar 

  7. Vesely I. Heart valve tissue engineering. Circ Res. 2005;97:743–55. https://doi.org/10.1161/01.RES.0000185326.04010.9f.

    Article  CAS  Google Scholar 

  8. Duncan AC, Boughner D, Vesely I. Dynamic glutaraldehyde fixation of a porcine aortic valve xenograft. I Effect of fixation conditions on the final tissue viscoelastic properties. Biomaterials. 1996;17:1849–56.

    Article  CAS  Google Scholar 

  9. Schenke-Layland K, Vasilevski O, Opitz F, König K, Riemann I, Halbhuber KJ, et al. Impact of decellularization of xenogeneic tissue on extracellular matrix integrity for tissue engineering of heart valves. J Struct Biol. 2003;143:201–8.

    Article  CAS  Google Scholar 

  10. Grauss RW, Hazekamp MG, Oppenhuizen F, van Munsteren CJ, Gittenberger-de Groot AC, DeRuiter MC. Histological evaluation of decellularised porcine aortic valves: matrix changes due to different decellularisation methods. Eur J Cardiothorac Surg. 2005;27:566–71. https://doi.org/10.1016/j.ejcts.2004.12.052.

    Article  Google Scholar 

  11. Goecke T, Theodoridis K, Tudorache I, Ciubotaru A, Cebotari S, Ramm R, et al. In vivo performance of freeze-dried decellularized pulmonary heart valve allo- and xenografts orthotopically implanted into juvenile sheep. Acta Biomater. 2018;68:41–52. https://doi.org/10.1016/j.actbio.2017.11.041.

    Article  Google Scholar 

  12. Parravicini R, Cocconcelli F, Verona A, Parravicini V, Giuliani E, Barbieri A. Tuna cornea as biomaterial for cardiac applications. Tex Heart Inst J. 2012;39:179–83.

    Google Scholar 

  13. Cebotari S, Mertsching H, Kallenbach K, Kostin S, Repin O, Batrinac A, et al. Construction of autologous human heart valves based on an acellular allograft matrix. Circulation. 2002;106:I63–8.

    Article  Google Scholar 

  14. Bader A, Schilling T, Teebken OE, Brandes G, Herden T, Steinhoff G, et al. Tissue engineering of heart valves: human endothelial cell seeding of detergent acellularized porcine valves. Eur J Cardiothorac Surg. 1998;14:279–84.

    Article  CAS  Google Scholar 

  15. Bertipaglia B, Ortolani F, Petrelli L, Gerosa G, Spina M, Pauletto P, 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. 2003;75:1274–82.

    Article  Google Scholar 

  16. Vincentelli A, Wautot F, Juthier F, Fouquet O, Corseaux D, Marechaux S, et al. In vivo autologous recellularization of a tissue-engineered heart valve: are bone marrow mesenchymal stem cells the best candidates? J Thorac Cardiovasc Surg. 2007;134:424–32. https://doi.org/10.1016/j.jtcvs.2007.05.005.

    Article  Google Scholar 

  17. Goldstein S, Clarke DR, Walsh SP, Black KS, O'Brien MF. Transpecies heart valve transplant: advanced studies of a bioengineered xeno-autograft. Ann Thorac Surg. 2000;70:1962–9.

    Article  CAS  Google Scholar 

  18. Elkins RC, Goldstein S, Hewitt CW, Walsh SP, Dawson PE, Ollerenshaw JD, et al. Recellularization of heart valve grafts by a process of adaptive remodeling. Semin Thorac Cardiovasc Surg. 2001;13:87–92.

    Article  CAS  Google Scholar 

  19. Simon P, Kasimir MT, Seebacher G, Weigel G, Ullrich R, Salzer-Muhar U, et al. Early failure of the tissue engineered porcine heart valve SYNERGRAFT in pediatric patients. Eur J Cardiothorac Surg. 2003;23:1002–6 discussion 1006.

    Article  CAS  Google Scholar 

  20. Konertz W, Angeli E, Tarusinov G, Christ T, Kroll J, Dohmen PM, et al. Right ventricular outflow tract reconstruction with decellularized porcine xenografts in patients with congenital heart disease. J Heart Valve Dis. 2011;20:341–7.

    Google Scholar 

  21. Teebken O, Mertsching H, Haverich A. Modification of heart valve allografts and xenografts by means of tissue engineering. Transplant Proc. 2002;34:2333.

    Article  CAS  Google Scholar 

  22. Cebotari S, Lichtenberg A, Tudorache I, Hilfiker A, Mertsching H, Leyh R, et al. Clinical application of tissue engineered human heart valves using autologous progenitor cells. Circulation. 2006;114:132–I-137. https://doi.org/10.1161/CIRCULATIONAHA.105.001065.

    Article  Google Scholar 

  23. Koenig F, Lee J, Akra B, Hollweck T, Wintermantel E, Hagl C, et al. Is Transcatheter aortic valve implantation of living tissue-engineered valves feasible? An in vitro evaluation utilizing a decellularized and reseeded biohybrid valve. Artif Organs. 2016;40:727–37. https://doi.org/10.1111/aor.12683.

    Article  CAS  Google Scholar 

  24. Sutherland FWH, Perry TE, Yu Y, Sherwood MC, Rabkin E, Masuda Y, et al. From stem cells to viable autologous semilunar heart valve. Circulation. 2005;111:2783–91. https://doi.org/10.1161/CIRCULATIONAHA.104.498378.

    Article  Google Scholar 

  25. Weber B, Scherman J, Emmert MY, Gruenenfelder J, Verbeek R, Bracher M, et al. Injectable living marrow stromal cell-based autologous tissue engineered heart valves: first experiences with a one-step intervention in primates. Eur Heart J. 2011;32:2830–40. https://doi.org/10.1093/eurheartj/ehr059.

    Article  Google Scholar 

  26. Syedain ZH, Bradee AR, Kren S, Taylor DA, Tranquillo RT. Decellularized tissue-engineered heart valve leaflets with recellularization potential. Tissue Eng Part A. 2013;19:759–69. https://doi.org/10.1089/ten.TEA.2012.0365.

    Article  CAS  Google Scholar 

  27. Motta SE, Fioretta ES, Dijkman PE, Lintas V, Behr L, Hoerstrup SP, et al. Development of an off-the-shelf tissue-engineered sinus valve for transcatheter pulmonary valve replacement: a proof-of-concept study. J Cardiovasc Transl Res. 2018;11:182–91. https://doi.org/10.1007/s12265-018-9800-6.

    Article  Google Scholar 

  28. Schmidt D, Achermann J, Odermatt B, Breymann C, Mol A, Genoni M, et al. Prenatally fabricated autologous human living heart valves based on amniotic fluid derived progenitor cells as single cell source. Circulation. 2007;116:64–I-70. https://doi.org/10.1161/CIRCULATIONAHA.106.681494.

    Article  Google Scholar 

  29. Schmidt D, Mol A, Breymann C, Achermann J, Odermatt B, Gössi M, et al. Living autologous heart valves engineered from human prenatally harvested progenitors. Circulation. 2006;114:125–I-131. https://doi.org/10.1161/CIRCULATIONAHA.105.001040.

    Article  Google Scholar 

  30. VeDepo MC, Detamore MS, Hopkins RA, Converse GL. Recellularization of decellularized heart valves: progress toward the tissue-engineered heart valve. Journal of Tissue Engineering. 2017. https://doi.org/10.1177/2041731417726327.

  31. Dong X, Wei X, Yi W, Gu C, Kang X, Liu Y, et al. RGD-modified acellular bovine pericardium as a bioprosthetic scaffold for tissue engineering. J Mater Sci Mater Med. 2009;20:2327–36. https://doi.org/10.1007/s10856-009-3791-4.

    Article  CAS  Google Scholar 

  32. Dijkman PE, Driessen-Mol A, Frese L, Hoerstrup SP, Baaijens FPT. Decellularized homologous tissue-engineered heart valves as off-the-shelf alternatives to xeno- and homografts. Biomaterials. 2012;33:4545–54. https://doi.org/10.1016/j.biomaterials.2012.03.015.

    Article  CAS  Google Scholar 

  33. Hof A, Raschke S, Baier K, Nehrenheim L, Selig JI, Schomaker M, et al. Challenges in develo** a reseeded, tissue-engineered aortic valve prosthesis. Eur J Cardiothorac Surg. 2016;50:446–55. https://doi.org/10.1093/ejcts/ezw057.

    Article  Google Scholar 

  34. Zhou J, Ye X, MD WZ, Liu J, Zhang B, Qiu J, et al. Development of decellularized aortic valvular conduit coated by heparin–SDF-1α multilayer. Ann Thorac Surg. 2015;99:612–8. https://doi.org/10.1016/j.athoracsur.2014.09.001.

    Article  Google Scholar 

  35. Ye X, Hu X, Wang H, Liu J, Zhao Q. Polyelectrolyte multilayer film on decellularized porcine aortic valve can reduce the adhesion of blood cells without affecting the growth of human circulating progenitor cells. Acta Biomater. 2012;8:1057–67. https://doi.org/10.1016/j.actbio.2011.11.011.

    Article  CAS  Google Scholar 

  36. Ye X, Wang H, Zhou J, Li H, Liu J, Wang Z, et al. The effect of heparin-VEGF multilayer on the biocompatibility of decellularized aortic valve with platelet and endothelial progenitor cells. PLoS One. 2013;8:e54622. https://doi.org/10.1371/journal.pone.0054622.

    Article  CAS  Google Scholar 

  37. Huang W, **ao D, Wang Y, Shan Z, Liu X, Lin Q, et al. Fn14 promotes differentiation of human mesenchymal stem cells into heart valvular interstitial cells by phenotypic characterization. J Cell Physiol. 2014;229:580–7. https://doi.org/10.1002/jcp.24480.

    Article  CAS  Google Scholar 

  38. Lichtenberg A, Cebotari S, Tudorache I, Sturz G, Winterhalter M, Hilfiker A, et al. Flow-dependent re-endothelialization of tissue-engineered heart valves. J Heart Valve Dis. 2006;15:287–94.

    Google Scholar 

  39. Lichtenberg A, Tudorache I, Cebotari S, Ringes-Lichtenberg S, Sturz G, Hoeffler K, et al. In vitro re-endothelialization of detergent decellularized heart valves under simulated physiological dynamic conditions. Biomaterials. 2006;27:4221–9. https://doi.org/10.1016/j.biomaterials.2006.03.047.

    Article  CAS  Google Scholar 

  40. Schenke-Layland K, Opitz F, Gross M, Döring C, Halbhuber KJ, Schirrmeister F, et al. Complete dynamic repopulation of decellularized heart valves by application of defined physical signals-an in vitro study. Cardiovasc Res. 2003;60:497–509. https://doi.org/10.1016/j.cardiores.2003.09.002.

    Article  CAS  Google Scholar 

  41. Converse GL, Buse EE, Neill KR, McFall CR, Lewis HN, VeDepo MC, et al. Design and efficacy of a single-use bioreactor for heart valve tissue engineering. J Biomed Mater Res Part B Appl Biomater. 2017;105:249–59. https://doi.org/10.1002/jbm.b.33552.

    Article  CAS  Google Scholar 

  42. Tudorache I, Calistru A, Baraki H, Meyer T, Höffler K, Sarikouch S, et al. Orthotopic replacement of aortic heart valves with tissue-engineered grafts. Tissue Eng Part A. 2013;19:1686–94. https://doi.org/10.1089/ten.tea.2012.0074.

    Article  CAS  Google Scholar 

  43. Kajbafzadeh A, Ahmadi Tafti SH, Mokhber-Dezfooli M, Khorramirouz R, Sabetkish S, Sabetkish N, et al. Aortic valve conduit implantation in the descending thoracic aorta in a sheep model: the outcomes of pre-seeded scaffold. Int J Surg. 2016;28:97–105. https://doi.org/10.1016/j.ijsu.2016.02.061.

    Article  Google Scholar 

  44. Ghodsizad A, Bordel V, Wiedensohler H, Elbanayosy A, Koerner MM, Gonzalez Berjon JM, et al. Magnetically guided recellularization of decellularized stented porcine pericardium-derived aortic valve for TAVI. ASAIO J. 2014;60:582–6. https://doi.org/10.1097/MAT.0000000000000110.

    Article  CAS  Google Scholar 

  45. Kluin J, Talacua H, Smits, Anthal IPM, Emmert MY, MCP B, et al. In situ heart valve tissue engineering using a bioresorbable elastomeric implant – from material design to 12 months follow-up in sheep. Biomaterials. 2017;125:101–17. https://doi.org/10.1016/j.biomaterials.2017.02.007.

    Article  CAS  Google Scholar 

  46. Bruder L, Spriestersbach H, Brakmann K, Stegner V, Sigler M, Berger F, et al. Transcatheter decellularized tissue-engineered heart valve (dTEHV) grown on polyglycolic acid (PGA) scaffold coated with P4HB shows improved functionality over 52 weeks due to polyether-ether-ketone (PEEK) insert. J Funct Biomater. 2018;9. https://doi.org/10.3390/jfb9040064.

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Sabin J. Bozso performed the literature search and wrote the manuscript. Jimmy J.H. Kang performed the literature search. Anoop Mathew, Michael C. Moon, Darren H. Freed, Jayan Nagendran and Jeevan Nagendran edited the manuscript.

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Correspondence to Sabin J. Bozso.

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Description of Future Works

Significant strides have been made in the design artificial heart valves. Ongoing studies will serve to establish the optimal scaffold design, leading to the generation of artificial heart valves that are durable, non-immunogenic, non-thrombotic, easily implantable, and readily available.

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Bozso, S.J., Kang, J.J.H., Mathew, A. et al. Comparing Scaffold Design and Recellularization Techniques for Development of Tissue Engineered Heart Valves. Regen. Eng. Transl. Med. 7, 432–439 (2021). https://doi.org/10.1007/s40883-020-00167-x

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