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Fast-degrading elastomer enables rapid remodeling of a cell-free synthetic graft into a neoartery

Nature Medicine volume 18, pages 1148–1153 (2012)Cite this article

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Abstract

Host remodeling is important for the success of medical implants, including vascular substitutes. Synthetic and tissue-engineered grafts have yet to show clinical effectiveness in arteries smaller than 5 mm in diameter. We designed cell-free biodegradable elastomeric grafts that degrade rapidly to yield neoarteries nearly free of foreign materials 3 months after interposition grafting in rat abdominal aorta. This design focuses on enabling rapid host remodeling. Three months after implantation, the neoarteries resembled native arteries in the following aspects: regular, strong and synchronous pulsation; a confluent endothelium and contractile smooth muscle layers; expression of elastin, collagen and glycosaminoglycan; and tough and compliant mechanical properties. Therefore, future studies employing large animal models more representative of human vascular regeneration are warranted before clinical translation. This cell-free approach represents a philosophical shift from the prevailing focus on cells in vascular tissue engineering and may have an impact on regenerative medicine in general.

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Figure 1: Characterization of the composite graft and host remodeling of the graft in vivo.
Figure 2: Smooth muscle cell infiltration and organization at 14 d.
Figure 3: Remodeling of grafts.
Figure 4: ECM organization and quantification at 90 d.
Figure 5: Endothelialization of the neoartery and vascular patency at day 90.

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References

  1. Weinberg, C.B. & Bell, E. A blood vessel model constructed from collagen and cultured vascular cells. Science 231, 397–400 (1986).

    Article  CAS  Google Scholar 

  2. Niklason, L.E. et al. Functional arteries grown in vitro. Science 284, 489–493 (1999).

    Article  CAS  Google Scholar 

  3. Dahl, S.L. et al. Readily available tissue-engineered vascular grafts. Sci. Transl. Med. 3, 68ra9 (2011).

    Article  Google Scholar 

  4. L'Heureux, N. et al. Human tissue-engineered blood vessels for adult arterial revascularization. Nat. Med. 12, 361–365 (2006).

    Article  CAS  Google Scholar 

  5. Kaushal, S. et al. Functional small-diameter neovessels created using endothelial progenitor cells expanded ex vivo. Nat. Med. 7, 1035–1040 (2001).

    Article  CAS  Google Scholar 

  6. Isenberg, B.C., Williams, C. & Tranquillo, R.T. Small-diameter artificial arteries engineered in vitro. Circ. Res. 98, 25–35 (2006).

    Article  CAS  Google Scholar 

  7. Hashi, C.K. et al. Antithrombogenic modification of small-diameter microfibrous vascular grafts. Arterioscler. Thromb. Vasc. Biol. 30, 1621–1627 (2010).

    Article  CAS  Google Scholar 

  8. Roh, J.D. et al. Tissue-engineered vascular grafts transform into mature blood vessels via an inflammation–mediated process of vascular remodeling. Proc. Natl. Acad. Sci. USA 107, 4669–4674 (2010).

    Article  CAS  Google Scholar 

  9. He, W. et al. Pericyte-based human tissue engineered vascular grafts. Biomaterials 31, 8235–8244 (2010).

    Article  CAS  Google Scholar 

  10. Neff, L.P. et al. Vascular smooth muscle enhances functionality of tissue-engineered blood vessels in vivo. J. Vasc. Surg. 53, 426–434 (2011).

    Article  Google Scholar 

  11. Zhu, C. et al. Development of anti-atherosclerotic tissue-engineered blood vessel by A20-regulated endothelial progenitor cells seeding decellularized vascular matrix. Biomaterials 29, 2628–2636 (2008).

    Article  CAS  Google Scholar 

  12. Long, J.L. & Tranquillo, R.T. Elastic fiber production in cardiovascular tissue-equivalents. Matrix Biol. 22, 339–350 (2003).

    Article  CAS  Google Scholar 

  13. Lee, K.W., Stolz, D.B. & Wang, Y. Substantial expression of mature elastin in arterial constructs. Proc. Natl. Acad. Sci. USA 108, 2705–2710 (2011).

    Article  CAS  Google Scholar 

  14. L'Heureux, N., McAllister, T.N. & de la Fuente, L.M. Tissue-engineered blood vessel for adult arterial revascularization. N. Engl. J. Med. 357, 1451–1453 (2007).

    Article  CAS  Google Scholar 

  15. Damus, P.S., Hicks, M. & Rosenberg, R.D. Anticoagulant action of heparin. Nature 246, 355–357 (1973).

    Article  CAS  Google Scholar 

  16. L'Heureux, N., Paquet, S., Labbe, R., Germain, L. & Auger, F.A. A completely biological tissue-engineered human blood vessel. FASEB J. 12, 47–56 (1998).

    Article  CAS  Google Scholar 

  17. Veith, F.J. et al. Six-year prospective multicenter randomized comparison of autologous saphenous vein and expanded polytetrafluoroethylene grafts in infrainguinal arterial reconstructions. J. Vasc. Surg. 3, 104–114 (1986).

    Article  CAS  Google Scholar 

  18. Ricardo, S.D., van Goor, H. & Eddy, A.A. Macrophage diversity in renal injury and repair. J. Clin. Invest. 118, 3522–3530 (2008).

    Article  CAS  Google Scholar 

  19. Mantovani, A., Garlanda, C. & Locati, M. Macrophage diversity and polarization in atherosclerosis: a question of balance. Arterioscler. Thromb. Vasc. Biol. 29, 1419–1423 (2009).

    Article  CAS  Google Scholar 

  20. Brown, B.N., Valentin, J.E., Stewart-Akers, A.M., McCabe, G.P. & Badylak, S.F. Macrophage phenotype and remodeling outcomes in response to biologic scaffolds with and without a cellular component. Biomaterials 30, 1482–1491 (2009).

    Article  CAS  Google Scholar 

  21. Turner, N.A., Hall, K.T., Ball, S.G. & Porter, K.E. Selective gene silencing of either MMP-2 or MMP-9 inhibits invasion of human saphenous vein smooth muscle cells. Atherosclerosis 193, 36–43 (2007).

    Article  CAS  Google Scholar 

  22. Verrier, E.D. & Boyle, E.M. Jr. Endothelial cell injury in cardiovascular surgery. Ann Thorac. Surg. 62, 915–922 (1996).

    Article  CAS  Google Scholar 

  23. Torikai, K. et al. A self-renewing, tissue-engineered vascular graft for arterial reconstruction. J. Thorac. Cardiovasc. Surg. 136, 37–45, 45 e31 (2008).

    Article  Google Scholar 

  24. Yokota, T. et al. In situ tissue regeneration using a novel tissue-engineered, small-caliber vascular graft without cell seeding. J. Thorac. Cardiovasc. Surg. 136, 900–907 (2008).

    Article  Google Scholar 

  25. Pavcnik, D. et al. Angiographic evaluation of carotid artery grafting with prefabricated small-diameter, small-intestinal submucosa grafts in sheep. Cardiovasc. Intervent. Radiol. 32, 106–113 (2009).

    Article  Google Scholar 

  26. Sandusky, G.E., Lantz, G.C. & Badylak, S.F. Healing comparison of small intestine submucosa and ePTFE grafts in the canine carotid artery. J. Surg. Res. 58, 415–420 (1995).

    Article  CAS  Google Scholar 

  27. Sandusky, G.E. Jr. Badylak, S.F., Morff, R.J., Johnson, W.D. & Lantz, G. Histologic findings after in vivo placement of small intestine submucosal vascular grafts and saphenous vein grafts in the carotid artery in dogs. Am. J. Pathol. 140, 317–324 (1992).

    PubMed Central  Google Scholar 

  28. Lantz, G.C., Badylak, S.F., Coffey, A.C., Geddes, L.A. & Blevins, W.E. Small intestinal submucosa as a small-diameter arterial graft in the dog. J. Invest. Surg. 3, 217–227 (1990).

    Article  CAS  Google Scholar 

  29. Prevel, C.D. et al. Experimental evaluation of small intestinal submucosa as a microvascular graft material. Microsurgery 15, 586–591; discussion 592–583 (1994).

    Article  CAS  Google Scholar 

  30. Huynh, T. et al. Remodeling of an acellular collagen graft into a physiologically responsive neovessel. Nat. Biotechnol. 17, 1083–1086 (1999).

    Article  CAS  Google Scholar 

  31. Soletti, L. et al. In vivo performance of a phospholipid-coated bioerodable elastomeric graft for small-diameter vascular applications. J. Biomed. Mater. Res. A 96, 436–448 (2011).

    Article  Google Scholar 

  32. Lee, C.H. et al. Regeneration of the articular surface of the rabbit synovial joint by cell homing: a proof of concept study. Lancet 376, 440–448 (2010).

    Article  CAS  Google Scholar 

  33. Li, L., Terry, C.M., Shiu, Y.T. & Cheung, A.K. Neointimal hyperplasia associated with synthetic hemodialysis grafts. Kidney Int. 74, 1247–1261 (2008).

    Article  CAS  Google Scholar 

  34. Discher, D.E., Janmey, P. & Wang, Y.L. Tissue cells feel and respond to the stiffness of their substrate. Science 310, 1139–1143 (2005).

    Article  CAS  Google Scholar 

  35. Zilla, P., Bezuidenhout, D. & Human, P. Prosthetic vascular grafts: wrong models, wrong questions and no healing. Biomaterials 28, 5009–5027 (2007).

    Article  CAS  Google Scholar 

  36. Bull, D.A. et al. Cellular origin and rate of endothelial cell coverage of PTFE grafts. J. Surg. Res. 58, 58–68 (1995).

    Article  CAS  Google Scholar 

  37. Hibino, N. et al. A critical role for macrophages in neovessel formation and the development of stenosis in tissue-engineered vascular grafts. FASEB J. 25, 4253–4263 (2011).

    Article  CAS  Google Scholar 

  38. Bernfield, M. et al. Functions of cell surface heparan sulfate proteoglycans. Annu. Rev. Biochem. 68, 729–777 (1999).

    Article  CAS  Google Scholar 

  39. Bezuidenhout, D. et al. Covalent surface heparinization potentiates porous polyurethane scaffold vascularization. J. Biomater. Appl. 24, 401–418 (2010).

    Article  CAS  Google Scholar 

  40. Wang, Y., Kim, Y.M. & Langer, R. In vivo degradation characteristics of poly(glycerol sebacate). J. Biomed. Mater. Res. A 66, 192–197 (2003).

    Article  Google Scholar 

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Acknowledgements

This research is supported by US National Institutes of Health (NIH) grant HL089658, American Heart Association award 0730031N and US NIH training grant 2T32HL076124. We thank S. Shroff for insightful discussions on mechanical testing of arteries, W. Wagner for access to the laser Doppler ultrasound and K. Kim for assistance with ultrasound imaging. We greatly appreciate R. Wagner and D. Rossi for performing angiography, M. Witt for DNA quantification, and D. Stolz, M. Sun and D. Clay for performing transmission electron microscopy.

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Authors and Affiliations

  1. Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Wei Wu, Robert A Allen & Yadong Wang

  2. Department of Maxillofacial Surgery, Qindu Hospital, Fourth Military Medical University, Xian, China

    Wei Wu

  3. Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Yadong Wang

  4. McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Yadong Wang

Authors
  1. Wei Wu
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Contributions

W.W. designed experiments, fabricated and implanted the grafts, characterized explants and analyzed data. R.A.A. performed mechanical characterization of grafts and explants, and analyzed data. Y.W. designed experiments and supervised the project. All authors interpreted results and contributed to writing the manuscript.

Corresponding author

Correspondence to Yadong Wang.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Table 1, Supplementary Figures 1–6 and Supplementary Methods (PDF 4922 kb)

Supplementary Video 1

Neo-artery pulses synchronously with host aorta (AVI 57182 kb)

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Wu, W., Allen, R. & Wang, Y. Fast-degrading elastomer enables rapid remodeling of a cell-free synthetic graft into a neoartery. Nat Med 18, 1148–1153 (2012). https://doi.org/10.1038/nm.2821

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