Skip to main content

Advertisement

SpringerLink
Log in

In-vivo-Züchtung von Herzklappengewebe

Entwicklung eines neuen Konzepts

In vivo tissue engineering of heart valves

Development of a new concept

  • Übersicht
  • Published:
Zeitschrift für Herz-,Thorax- und Gefäßchirurgie Aims and scope

Zusammenfassung

Aktuell werden für die Züchtung von Herzklappengewebe („tissue engineering“) aus Patienten gewonnene Zellen oder Stammzellen verwendet, die in vitro vor der Implantation auf verschiedenen Matrizes angesiedelt werden. Nachteile bei diesen Verfahren sind die lange In-vitro-Kultivierungsdauer, das während dieser Zeit bestehende Infektionsrisiko und die aufwändige und kostenintensive Ausstattung. Mit einer Off-the-shelf-Herzklappe mit In-vivo-Endothelialisierungs- und Regenerationspotenzial könnten diese Limitierungen umgangen werden. Außerdem würde die Entwicklung einer Herzklappe mit Wachstumspotenzial eine enorme Verbesserung für pädiatrische Patienten bedeuten. Dieser Artikel diskutiert verschiedene Startermatrizes, Homing- und Immobilisierungsstrategien von Patientenzellen sowie Maskierungsmöglichkeiten für inflammatorische Strukturen für das In-vivo-Oberflächen- und -Tissue-Engineering (TE) von Herzklappen. Zusätzlich wird ein neues Konzept vorgestellt, das auf der Immobilisierung von hochspezifischen DNA-Aptameren auf der Herzklappenmatrix basiert, die als Fängermoleküle für im Blut zirkulierende endotheliale Progenitorzellen (EPC) fungieren.

Abstract

Currently pursued tissue engineering principles of heart valves require tissue or stem cell-derived autologous cells with subsequent in vitro incubation on matrix scaffolds. Limitations of this approach are a long in vitro culture, a constantly accompanied risk of infection, and the requirement of a sophisticated, cost intensive infrastructure. An “off-the-shelf” heart valve with in vivo endothelialization and tissue regeneration potential represents an attractive alternative to overcome these limitations. Particularly for the pediatric patients, the development of heart valves with growth potential would significantly improve current treatment options. This article discusses different starter matrices, homing and immobilization strategies of host cells, and masking approaches of inflammation for in vivo surface and tissue engineering of heart valves. A novel concept based on highly specific DNA aptamers immobilized on the heart valve surface as capture molecules for endothelial progenitor cells (EPCs) circulating in the blood stream is presented.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2

Literatur

  1. Peterseim DS, Cen YY, Cheruvu S et al (1999) Long-term outcome after biologic versus mechanical aortic valve replacement in 841 patients. J Thorac Cardiovasc Surg 117(5):890–897

    Article  CAS  PubMed  Google Scholar 

  2. Gao G, Wu Y, Grunkemeier GL et al (2004) Durability of pericardial versus porcine aortic valves. J Am Coll Cardiol 44(2):384–388

    Article  PubMed  Google Scholar 

  3. Brown JM, O’Brien SM, Wu C et al (2009) Isolated aortic valve replacement in North America comprising 108,687 patients in 10 years: changes in risks, valve types, and outcomes in the society of thoracic surgeons National Database. J Thorac Cardiovasc Surg 137(1):82–90

    Article  PubMed  Google Scholar 

  4. Vongpatanasin W, Hillis LD, Lange RA (1996) Prosthetic Heart Valves. N Engl J Med 335(6):407–416

    Article  CAS  PubMed  Google Scholar 

  5. Hammermeister KE, Sethi GK, Henderson WG et al (1993) A comparison of outcomes in men 11 years after heart-valve replacement with a mechanical valve or bioprosthesis. Veterans affairs cooperative study on valvular heart disease. N Engl J Med 328(18):1289–1296

    Article  CAS  PubMed  Google Scholar 

  6. Mestres CA, Agusti E, Martinez A et al (2000) Cardiovascular tissue banking in the non-cadaveric setting: ten-year experience of a university hospital-based bank with active organ donation program. J Heart Valve Dis 9(4):523–529

    CAS  PubMed  Google Scholar 

  7. Wetli CV, Kolovich RM, Dinhofer L (2002) Modified cardiectomy: documenting sudden cardiac death in hearts selected for valve allograft procurement. Am J Forensic Med Pathol 23(2):137–141

    Article  PubMed  Google Scholar 

  8. Gulbins H, Kreuzer E, Reichart B (2003) Homografts: A Review. Expert Rev Cardiovasc Ther 1(4):533–539

    Article  PubMed  Google Scholar 

  9. Mayer JE Jr (2001) In search of the ideal valve replacement device. J Thorac Cardiovasc Surg 122(1):8–9

    Article  PubMed  Google Scholar 

  10. Langer R, Vacanti JP (1993) Tissue engineering. Science 260(5110):920–926

    Article  CAS  PubMed  Google Scholar 

  11. Stock UA, Mayer JE Jr (1999) Valves in development for autogenous tissue valve replacement. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2:51–64

    PubMed  Google Scholar 

  12. Steinhoff G, Stock U, Karim N et al (2000) Tissue engineering of pulmonary heart valves on allogenic acellular matrix conduits: in vivo restoration of valve tissue. Circulation 102(19 Suppl 3):III50–III55

    CAS  PubMed  Google Scholar 

  13. Schenke-Layland K, Opitz F, Gross M et al (2003) Complete dynamic repopulation of decellularized heart valves by application of defined physical signals-an in vitro study. Cardiovasc Res 60(3):497–509

    Article  CAS  PubMed  Google Scholar 

  14. Sutherland FW, Perry TE, Yu Y et al (2005) From stem cells to viable autologous semilunar heart valve. Circulation 111(21):2783–2791

    Article  PubMed  Google Scholar 

  15. Gummert JF, Funkat A, Beckmann A et al (2008) Cardiac surgery in Germany during 2007: A report on behalf of the German Society for thoracic and cardiovascular surgery. Thorac Cardiovasc Surg 56(6):328–336

    Article  CAS  PubMed  Google Scholar 

  16. Breuer CK, Mettler BA, Anthony T et al (2004) Application of tissue-engineering principles toward the development of a semilunar heart valve substitute. Tissue Eng 10(11–12):1725–1736

    Google Scholar 

  17. Dohmen PM, Costa F, Lopes SV et al (2005) Results of a decellularized porcine heart valve implanted into the juvenile sheep model. Heart Surg Forum 8(2):E100–E104; discussion E104

    Article  CAS  PubMed  Google Scholar 

  18. Bader A, Schilling T, Teebken OE et al (1998) Tissue engineering of heart valves – human endothelial cell seeding of detergent acellularized porcine valves. Eur J Cardiothorac Surg 14(3):279–284

    Article  CAS  PubMed  Google Scholar 

  19. Elkins RC, Dawson PE, Goldstein S et al (2001) Decellularized human valve allografts. Ann Thorac Surg 71(5 Suppl):S428–S432

    Article  CAS  PubMed  Google Scholar 

  20. Goldstein S, Clarke DR, Walsh SP et al (2000) Transpecies heart valve transplant: advanced studies of a bioengineered xeno-autograft. Ann Thorac Surg 70(6):1962–1969

    Article  CAS  PubMed  Google Scholar 

  21. Simon P, Kasimir MT, Seebacher G et al (2003) Early failure of the tissue engineered porcine heart valve synergraft in pediatric patients. Eur J Cardiothorac Surg 23(6):1002–1006; discussion 1006

    Article  CAS  PubMed  Google Scholar 

  22. Bechtel JF, Stierle U, Sievers HH (2008) Fifty-two months‘ mean follow up of decellularized synergraft-treated pulmonary valve allografts. J Heart Valve Dis 17(1):98–104; discussion 104

    PubMed  Google Scholar 

  23. Dohmen PM, Hauptmann S, Terytze A, Konertz WF (2007) In-vivo repopularization of a tissue-engineered heart valve in a human subject. J Heart Valve Dis 16(4):447–449

    PubMed  Google Scholar 

  24. Cebotari S, Lichtenberg A, Tudorache I et al (2006) Clinical application of tissue engineered human heart valves using autologous progenitor cells. Circulation 114(1 Suppl):I132–I137

    Article  PubMed  Google Scholar 

  25. Juthier F, Vincentelli A, Gaudric J et al (2006) Decellularized heart valve as a scaffold for in vivo recellularization: Deleterious effects of granulocyte colony-stimulating factor. J Thorac Cardiovasc Surg 131(4):843–852

    Article  CAS  PubMed  Google Scholar 

  26. Felker GM, Milano CA, Yager JE et al (2005) Outcomes with an alternate list strategy for heart transplantation. J Heart Lung Transplant 24(11):1781–1786

    Article  PubMed  Google Scholar 

  27. Matheny RG, Hutchison ML, Dryden PE et al (2000) Porcine small intestine submucosa as a pulmonary valve leaflet substitute. J Heart Valve Dis 9(6):769–774; discussion 774–765

    CAS  PubMed  Google Scholar 

  28. Kasimir MT, Rieder E, Seebacher G et al (2006) Decellularization does not eliminate thrombogenicity and inflammatory stimulation in tissue-engineered porcine heart valves. J Heart Valve Dis 15(2):278–286; discussion 286

    PubMed  Google Scholar 

  29. de Mel A, Jell G, Stevens MM, Seifalian AM (2008) Biofunctionalization of biomaterials for accelerated in situ endothelialization: A review. Biomacromolecules 9(11):2969–2979

    Article  Google Scholar 

  30. Walluscheck KP, Steinhoff G, Kelm S, Haverich A (1996) Improved endothelial cell attachment on eptfe vascular grafts pretreated with synthetic Rgd-containing peptides. Eur J Vasc Endovasc Surg 12(3):321–330

    Article  CAS  PubMed  Google Scholar 

  31. Blindt R, Vogt F, Astafieva I et al (2006) A novel drug-eluting stent coated with an integrin-binding cyclic arg-gly-asp peptide inhibits neointimal hyperplasia by recruiting endothelial progenitor cells. J Am Coll Cardiol 47(9):1786–1795

    Article  CAS  PubMed  Google Scholar 

  32. Meinhart JG, Schense JC, Schima H et al (2005) Enhanced endothelial cell retention on shear-stressed synthetic vascular grafts precoated with Rgd-cross-linked fibrin. Tissue Eng 11(5–6):887–895

    Google Scholar 

  33. Rotmans JI, Heyligers JM, Verhagen HJ et al (2005) In Vivo cell seeding with anti-cd34 antibodies successfully accelerates endothelialization but stimulates intimal hyperplasia in porcine arteriovenous expanded polytetrafluoroethylene grafts. Circulation 112(1):12–18

    Article  CAS  PubMed  Google Scholar 

  34. Wojciechowski JC, Narasipura SD, Charles N et al (2008) Capture and enrichment of Cd34-positive haematopoietic stem and progenitor cells from blood circulation using P-Selectin in an implantable device. Br J Haematol 140(6):673–681

    Article  PubMed  Google Scholar 

  35. Wu S, Liu YL, Cui B et al (2007) Study on decellularized porcine aortic valve/poly (3-Hydroxybutyrate-Co-3-Hydroxyhexanoate) hybrid heart valve in sheep model. Artif Organs 31(9):689–697

    Article  PubMed  Google Scholar 

  36. Stamm C, Khosravi A, Grabow N et al (2004) Biomatrix/Polymer composite material for heart valve tissue engineering. Ann Thorac Surg 78(6):2084–2092; discussion 2092–2083

    Article  PubMed  Google Scholar 

  37. Tedder ME, Liao J, Weed B et al (2009) Stabilized collagen scaffolds for heart valve tissue engineering. Tissue Eng Part A 15(6):1257–1268

    Article  CAS  PubMed  Google Scholar 

  38. Crombez M, Chevallier P, Gaudreault RC et al (2005) Improving arterial prosthesis neo-endothelialization: Application of a proactive vegf construct onto ptfe surfaces. Biomaterials 26(35):7402–7409

    Article  CAS  PubMed  Google Scholar 

  39. Hristov M, Erl W, Weber PC (2003) Endothelial progenitor cells: mobilization, differentiation, and homing. Arterioscler Thromb Vasc Biol 23(7):1185–1189

    Article  CAS  PubMed  Google Scholar 

  40. Frid MG, Kale VA, Stenmark KR (2002) Mature vascular endothelium can give rise to smooth muscle cells via endothelial-mesenchymal transdifferentiation: In Vitro analysis. Circ Res 90(11):1189–1196

    Article  CAS  PubMed  Google Scholar 

  41. Meinhart JG, Deutsch M, Fischlein T et al (2001) Clinical autologous in vitro endothelialization of 153 infrainguinal eptfe grafts. Ann Thorac Surg 71(5 Suppl):S327–S331

    Article  CAS  PubMed  Google Scholar 

  42. Thomas AC, Campbell GR, Campbell JH (2003) Advances in vascular tissue engineering. Cardiovasc Pathol 12(5):271–276

    Article  CAS  PubMed  Google Scholar 

  43. Kasimir MT, Weigel G, Sharma J et al (2005) The decellularized porcine heart valve matrix in tissue engineering: Platelet adhesion and activation. Thromb Haemost 94(3):562–567

    CAS  PubMed  Google Scholar 

  44. Thomas HE, Redgrave R, Cunnington MS et al (2008) Circulating endothelial progenitor cells exhibit diurnal variation. Arterioscler Thromb Vasc Biol 28(3):e21–e22

    Article  CAS  PubMed  Google Scholar 

  45. Hattori K, Heissig B, Tashiro K et al (2001) Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells. Blood 97(11):3354–3360

    Article  CAS  PubMed  Google Scholar 

  46. Wojakowski W, Ratajczak MZ, Tendera M (2006) Interleukin-8: more on the mechanisms of progenitor cells mobilization in acute coronary syndromes. Eur Heart J 27(9):1013–1015

    Article  PubMed  Google Scholar 

  47. Aicher A, Zeiher AM, Dimmeler S (2005) Mobilizing endothelial progenitor cells. Hypertension 45(3):321–325

    Article  CAS  PubMed  Google Scholar 

  48. Hoffmann J, Groll J, Heuts J et al (2006) Blood cell and plasma protein repellent properties of Star-Peg-Modified Surfaces. J Biomater Sci Polym Ed 17(9):985–996

    Article  CAS  PubMed  Google Scholar 

  49. Wilson DS, Szostak JW (1999) In Vitro selection of functional nucleic acids. Annu Rev Biochem 68:611–647

    Article  CAS  PubMed  Google Scholar 

  50. Nimjee SM, Rusconi CP, Sullenger BA (2005) Aptamers: an emerging class of therapeutics. Annu Rev Med 56:555–583

    Article  CAS  PubMed  Google Scholar 

  51. Brody EN, Gold L (2000) Aptamers as therapeutic and diagnostic agents. J Biotechnol 74(1):5–13

    CAS  PubMed  Google Scholar 

  52. Tuerk C, Gold L (1990) Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA Polymerase. Science 249(4968):505–510

    Article  CAS  PubMed  Google Scholar 

  53. Chandler AB (1958) In Vitro thrombotic coagulation of the Blood; a method for producing a Thrombus. Lab Invest 7(2):110–114

    CAS  PubMed  Google Scholar 

  54. Hoffmann J, Paul A, Harwardt M et al (2008) Immobilized DNA aptamers used as potent attractors for porcine endothelial precursor cells. J Biomed Mater Res A 84(3):614–621

    PubMed  Google Scholar 

  55. Zilla P, Fullard L, Trescony P et al (1997) Glutaraldehyde detoxification of aortic wall tissue: A promising perspective for emerging bioprosthetic valve concepts. J Heart Valve Dis 6(5):510–520

    CAS  PubMed  Google Scholar 

  56. Groll J, Ameringer T, Spatz JP, Moeller M (2005) Ultrathin coatings from isocyanate-terminated star peg prepolymers: Layer formation and characterization. Langmuir 21(5):1991–1999

    Article  CAS  PubMed  Google Scholar 

Download references

Interessenkonflikt

Der Autor gibt an, dass kein Interessenkonflikt besteht.

Author information

Authors and Affiliations

  1. Klinik für Thorax-, Herz- und Gefäßchirurgie, Universitätsklinik Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Deutschland

    M. Schleicher, H.-P. Wendel, A.J. Huber, O. Fritze &  U.A. Stock

Authors
  1. M. Schleicher
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H.-P. Wendel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A.J. Huber
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. O. Fritze
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. U.A. Stock
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to U.A. Stock.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schleicher, M., Wendel, HP., Huber, A. et al. In-vivo-Züchtung von Herzklappengewebe. Z Herz- Thorax- Gefäßchir 24, 6–13 (2010). https://doi.org/10.1007/s00398-009-0753-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00398-009-0753-6

Schlüsselwörter

Keywords

Search

Navigation