Cardiovascular Engineering and Technology

, Volume 2, Issue 2, pp 113–123 | Cite as

Sustained Delivery of Nitric Oxide from Poly(ethylene glycol) Hydrogels Enhances Endothelialization in a Rat Carotid Balloon Injury Model



The continuing high incidence of vascular disease is leading to a greater need for interventional therapies and vascular prostheses. Nitric oxide (NO), which has been heavily investigated in recent years as an important biological mediator, is presented in this work as a sustained localized therapeutic for vascular disorders, specifically in the prevention of restenosis. NO-releasing PEG hydrogels were applied to the outer surfaces of carotid arteries following balloon denudation in a rat animal model. NO was allowed to diffuse into the vessel, and intimal thickening, as assessed after 2 and 28 days, was almost fully eliminated, showing an approximate 90% decrease. Meanwhile, endothelial cell migration and proliferation into the damaged vessel sections were observed. These results signify that these materials are suitable to prevent intimal hyperplasia and induce endothelialization in vivo, making these NO-releasing hydrogels an ideal candidate for incorporation into blood-contacting devices for the prevention of restenosis.


Nitric oxide Endothelialization Hydrogel Poly(ethylene glycol) Diazeniumdiolate 



Research funding was provided by an NSF CAREER Award [BES-9875607], the Rice University Alliance for Graduate Education and the Professoriate (AGEP) [NSF Cooperative Agreement No. [HRD-9817555], and the Rice University Integrative Graduate Education and Research Traineeship [NSF IGERT Grant 0114264].

Conflicts of interest

No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.


  1. 1.
    Agata, J., J. J. Zhang, J. Chao, and L. Chao. Adrenomedullin gene delivery inhibits neointima formation in rat artery after balloon angioplasty. Regul. Pept. 112:115–120, 2003.CrossRefGoogle Scholar
  2. 2.
    Bailey, S. R. Local drug delivery: current applications. Prog. Cardiovasc. Dis. 40:183–204, 1997.CrossRefGoogle Scholar
  3. 3.
    Bauters, C., and J. M. Isner. The biology of restenosis. Prog. Cardiovasc. Dis. 40(2):107–116, 1997.CrossRefGoogle Scholar
  4. 4.
    Bohl, K. S., and J. L. West. Nitric oxide-generating polymers reduce platelet adhesion and smooth muscle cell proliferation. Biomaterials 21:2273–2278, 2000.CrossRefGoogle Scholar
  5. 5.
    Bult, H. Restenosis: a challenge for pharmacology. Trends Pharmacol. Sci. 21(7):274–279, 2000.CrossRefGoogle Scholar
  6. 6.
    Dangas, G. D., B. E. Claessen, A. Caixeta, E. A. Sanidas, G. S. Mintz, and R. Mehran. In-stent restenosis in the drug-eluting stent era. J. Am. Coll. Cardiol. 56:1897–1907, 2010.CrossRefGoogle Scholar
  7. 7.
    Elkins, C. J., J. M. Waugh, P. G. Amabile, H. Minamiguchi, M. Uy, K. Sugimoto, et al. Development of a platform to evaluate and limit in-stent restenosis. Tissue Eng. 8:395–407, 2002.CrossRefGoogle Scholar
  8. 8.
    Ettenson, D. S., and E. R. Edelman. Local drug delivery: an emerging approach in the treatment of restenosis. Vasc. Med. 5:97–102, 2000.Google Scholar
  9. 9.
    Fattori, R., and T. Piva. Drug-eluting stents in vascular intervention. Lancet 361:247–249, 2003.CrossRefGoogle Scholar
  10. 10.
    Folts, J. D., and J. Loscalzo. Coating arterial and blood-contacting surfaces with NO-donating materials. In: Nitric Oxide and the Cardiovascular System, edited by J. Loscalzo, and J. A. Vita. Totowa, NJ: Humana Press, 2000, pp. 503–514.CrossRefGoogle Scholar
  11. 11.
    Herrmann, R., G. Schmidmaier, B. Markl, A. Resch, I. Hahnel, A. Stemberger, et al. Antithrombogenic coating of stents using a biodegradable drug delivery technology. Thromb. Haemost. 82:51–57, 1999.Google Scholar
  12. 12.
    Hrabie, J. A., J. R. Klose, D. A. Wink, and L. K. Keefer. New nitric oxide-releasing zwitterions derived from polyamines. J. Org. Chem. 58:1472–1476, 1993.CrossRefGoogle Scholar
  13. 13.
    Jun, H. W., L. J. Taite, and J. L. West. Nitric oxide-producing polyurethanes. Biomacromolecules 6:838–844, 2005.CrossRefGoogle Scholar
  14. 14.
    Kapadia, M. R., L. W. Chow, N. D. Tsihlis, S. S. Ahanchi, J. W. Eng, J. Murar, et al. Nitric oxide and nanotechnology: a novel approach to inhibit neointimal hyperplasia. J. Vasc. Surg. 47:173–182, 2008.CrossRefGoogle Scholar
  15. 15.
    Kavanagh, C. A., Y. A. Rochev, W. M. Gallagher, K. A. Dawson, and A. K. Keenan. Local drug delivery in restenosis injury: thermoresponsive co-polymers as potential drug delivery systems. Pharmacol. Ther. 102:1–15, 2004.CrossRefGoogle Scholar
  16. 16.
    Keefer, L. K. Progress toward clinical application of the nitric oxide-releasing diazeniumdiolates. Annu. Rev. Pharmacol. Toxicol. 43:585–607, 2003.CrossRefGoogle Scholar
  17. 17.
    Kelm, M. Nitric oxide metabolism and breakdown. Biochim. Biophys. Acta 1411:273–289, 1999.CrossRefGoogle Scholar
  18. 18.
    Lee, M. S., E. M. David, R. R. Makkar, and J. R. Wilentz. Molecular and cellular basis of restenosis after percutaneous coronary intervention: the intertwining roles of platelets, leukocytes, and the coagulation-fibrinolysis system. J. Pathol. 203:861–870, 2004.CrossRefGoogle Scholar
  19. 19.
    Lipke, E. A., and J. L. West. Localized delivery of nitric oxide from hydrogels inhibits neointima formation in a rat carotid balloon injury model. Acta Biomater. 1(6):597–606, 2005.CrossRefGoogle Scholar
  20. 20.
    Majesky, M. W., C. M. Giachelli, M. A. Reidy, and S. M. Schwartz. Rat carotid neointimal smooth muscle cells reexpress a developmentally regulated mRNA phenotype during repair of arterial injury. Circ. Res. 71:759–768, 1992.Google Scholar
  21. 21.
    Masters, K. S., E. A. Lipke, E. E. Rice, M. S. Liel, H. A. Myler, C. Zygourakis, et al. Nitric oxide-generating hydrogels inhibit neointima formation. J. Biomater. Sci. Polym. Ed. 16:659–672, 2005.CrossRefGoogle Scholar
  22. 22.
    Moore, S. Amino acid analysis: aqueous dimethyl sulfoxide as solvent for the ninhydrin reaction. J. Biol. Chem. 243:6281–6283, 1968.Google Scholar
  23. 23.
    Pearce, C. G., S. F. Najjar, M. R. Kapadia, J. Murar, J. Eng, B. Lyle, et al. Beneficial effect of a short-acting NO donor for the prevention of neointimal hyperplasia. Free Radic. Biol. Med. 44:73–81, 2008.CrossRefGoogle Scholar
  24. 24.
    Raman, V. K., and E. R. Edelman. Coated stents: local pharmacology. Semin. Interv. Cardiol. 3:133–137, 1998.Google Scholar
  25. 25.
    Saavedra, J. E., D. L. Mooradian, K. A. Mowery, M. H. Schoenfisch, M. L. Citro, K. M. Davies, et al. Conversion of a polysaccharide to nitric oxide-releasing form. Dual-mechanism anticoagulant activity of diazeniumdiolated heparin. Bioorg. Med. Chem. Lett. 10(8):751–753, 2000.CrossRefGoogle Scholar
  26. 26.
    Sharma, S., C. Christopoulos, N. Kukreja, and D. A. Gorog. Local drug delivery for percutaneous coronary intervention. Pharmacol. Ther. 2010Google Scholar
  27. 27.
    Taite, L. J., P. Yang, H. W. Jun, and J. L. West. Nitric oxide-releasing polyurethane-PEG copolymer containing the YIGSR peptide promotes endothelialization with decreased platelet adhesion. J. Biomed. Mater. Res. B Appl. Biomater. 84(1):108–116, 2008.Google Scholar
  28. 28.
    Takamiya, Y., S. I. Miura, Y. Tsuchiya, Y. Fukuda, B. Zhang, T. Kuwano, et al. Angiographic late lumen loss at the site of overlap of multiple Cypher sirolimus-eluting stents: ALSOCE study. J. Cardiol. 2010Google Scholar
  29. 29.
    Tanabe, K., E. Regar, C. H. Lee, A. Hoye, W. J. van der Giessen, and P. W. Serruys. Local drug delivery using coated stents: new developments and future perspectives. Curr. Pharm. Des. 10:357–367, 2004.CrossRefGoogle Scholar
  30. 30.
    Virmani, R., F. D. Kolodgie, A. Farb, and A. Lafont. Drug eluting stents: are human and animal studies comparable? Heart 89:133–138, 2003.CrossRefGoogle Scholar
  31. 31.
    Walter, D. H., M. Cejna, L. Diaz-Sandoval, S. Willis, L. Kirkwood, P. W. Stratford, et al. Local gene transfer of phVEGF-2 plasmid by gene-eluting stents: an alternative strategy for inhibition of restenosis. Circulation 110:36–45, 2004.CrossRefGoogle Scholar
  32. 32.
    West, J. L., and J. A. Hubbell. Separation of the arterial wall from blood contact using hydrogel barriers reduces intimal thickening after balloon injury in the rat: the roles of medial and luminal factors in arterial healing. Proc. Natl Acad. Sci. U.S.A. 93:13188–13193, 1996.CrossRefGoogle Scholar

Copyright information

© Biomedical Engineering Society 2011

Authors and Affiliations

  1. 1.School of Chemical & Biomolecular EngineeringGeorgia Institute of TechnologyAtlantaUSA
  2. 2.Department of BioengineeringRice UniversityHoustonUSA

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