Skip to main content
SpringerLink
Log in

Crosslinking effect of Nordihydroguaiaretic acid (NDGA) on decellularized heart valve scaffold for tissue engineering

  • Published:
Journal of Materials Science: Materials in Medicine Aims and scope Submit manuscript

Abstract

Decellularized heart valve scaffolds possess many desirable properties in valvular tissue engineering. However, their current applications were limited by short durability, easily structural dysfunction and immunological competence. Although crosslinking with chemical reagents, such as glutaraldehyde (GA), will enhance the mechanical properties, the low long-term stability and cytotoxicity of the scaffolds remains potential problem. Nordihydroguaiaretic acid (NDGA) is a bioactive natural product which is able to crosslink collagen and was proven to be effective in preparation of scaffold for tendon tissue engineering. In this paper, NDGA crosslinked decellularized heart valve scaffolds demonstrated higher tensile strength, enzymatic hydrolysis resistance and store stability than the non-crosslinked ones. Its mechanical properties and cytocompability were superior to that of GA-crosslinked heart valve matrix. Below the concentration of 10 μg/ml, NDGA has no visible cytotoxic effect on both endothelial cells (EC) and valvular interstitial cells (VIC) and its cytotoxicity is much less than that of GA. The LC50 (50% lethal concentration) of NDGA on ECs and VICs are 32.6 μg/ml and 47.5 μg/ml, respectively, while those of GA are almost 30 times higher than NDGA (P < 0.05). ECs can attach to and maintain normal morphology on the surface of NDGA-crosslinked valvular scaffolds but not GA-crosslinked ones. This study demonstrated that NDGA-crosslinking of decellularized valvular matrix is a promising approach for preparation of heart valve tissue engineering scaffolds.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Brody S, Pandit A. Approaches to heart valve tissue engineering scaffold design. J Biomed Mater Res B. 2007;83B:16–43.

    Article  CAS  Google Scholar 

  2. Schoen FJ, Levy RJ. Founder’s Award, 25th Annual Meeting of the Society for Biomaterials, perspectives. Providence, RI, April 28-May 2, 1999. Tissue heart valves: current challenges and future research perspectives. J Biomed Mater Res. 1999;47:439–65.

    Article  CAS  PubMed  Google Scholar 

  3. Hopkins PA. Tissue engineering of heart valves: decellularized valve scaffolds. Circulation. 2005;111:2712–4.

    Article  PubMed  Google Scholar 

  4. Kidane AG, Burriesci G, Cornejo P, Dooley A, Sarkar S, Bonhoeffer P, et al. Current developments and future prospects for heart valve replacement therapy. J Biomed Mater Res B. 2009;88B:290–303.

    Article  CAS  Google Scholar 

  5. Kim SS, Lim SH, Cho SW, Gwak SJ, Hong YS, Chang BC, et al. Tissue engineering of heart valves by recellularization of glutaraldehyde-fixed porcine valves using bone marrow-derived cells. Exp Mol Med. 2006;38:273–83.

    CAS  PubMed  Google Scholar 

  6. Lee CH, Jang YS, Her SJ, Moon YM, Baek SJ, Eling T. Nordihydroguaiaretic acid, an antioxidant, inhibits transforming growth factor-beta activity through the inhibition of Smad signaling pathway. Exp Cell Res. 2003;289:335–41.

    Article  CAS  PubMed  Google Scholar 

  7. Lambert JD, Dorr RT, Timmermann BN. Nordihydroguaiaretic acid: a review of its numerous and varied biological activities. Pharm Biol. 2004;42:149–58.

    Article  CAS  Google Scholar 

  8. Goodman Y, Steiner MR, Steiner SM, Mattson MP. Nordihydroguaiaretic acid protects hippocampal neurons against amyloid beta-peptide toxicity, and attenuates free radical and calcium accumulation. Brain Res. 1994;654:171–6.

    Article  CAS  PubMed  Google Scholar 

  9. Arteaga S, Andrade-Cetto A, Cárdenas R. Larrea tridentata (Creosote bush), an abundant plant of Mexican and US-American deserts and its metabolite Nordihydroguaiaretic acid. J Ethnopharmacol. 2005;98:231–9.

    Article  CAS  PubMed  Google Scholar 

  10. Koob TJ, Willis TA, Hernandez DJ. Biocompatibility of NDGA-polymerized collagen fibers. I. Evaluation of cytotoxicity with tendon fibroblasts in vitro. J Biomed Mater Res. 2001;56:31–9.

    Article  CAS  PubMed  Google Scholar 

  11. Koob TJ, Hernandez DJ. Material properties of polymerized NDGA-collagen composite fibers: development of biologically based tendon constructs. Biomaterials. 2002;23:203–12.

    Article  CAS  PubMed  Google Scholar 

  12. Koob TJ, Willis TA, Qiu YS, Hernandez DJ. Biocompatibility of NDGA-polymerized collagen fibers. II. Attachment, proliferation, and migration of tendon fibroblasts in vitro. J Biomed Mater Res. 2001;56:40–8.

    Article  CAS  PubMed  Google Scholar 

  13. Koob TJ, Hernandez DJ. Mechanical and thermal properties of novel polymerized NDGA-gelatin hydrogels. Biomaterials. 2003;24:1285–92.

    Article  CAS  PubMed  Google Scholar 

  14. Pennisi E. Tending tender tendons. Science. 2002;295:1011.

    Article  CAS  PubMed  Google Scholar 

  15. Meyer SR, Chiu B, Churchill TA, Zhu L, Lakey JR, Ross DB. Comparison of aortic valve allograft decellularization techniques in the rat. J Biomed Mater Res A. 2006;79A:254–62.

    Article  CAS  Google Scholar 

  16. Hyder PW, Fredrickson EL, Estell RE, Tellez M, Gibbens RP. Distribution and concentration of total phenolics, condensed tannins, and Nordihydroguaiaretic acid (NDGA) in creosotebush (Larrea tridentata). Biochem Syst Ecol. 2002;30:905–12.

    Article  CAS  Google Scholar 

  17. Liang HC, Chang Y, Hsu CK, Lee MH, Sung HW. Effects of crosslinking degree of an acellular biological tissue on its tissue regeneration pattern. Biomaterials. 2004;25:3541–52.

    Article  CAS  PubMed  Google Scholar 

  18. Teebken OE, Bader A, Steinhoff G, Haverich A. Tissue engineering of vascular grafts: human cell seeding of decellularised porcine matrix. Eur J Vasc Endovasc. 2000;19:381–6.

    Article  CAS  Google Scholar 

  19. 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  PubMed  Google Scholar 

  20. Zhai W, Chang J, Lin K, Wang J, Zhao Q, Sun X. Crosslinking of decellularized porcine heart valve matrix by procyanidins. Biomaterials. 2006;27:3684–90.

    CAS  PubMed  Google Scholar 

  21. Han B, Jaurequi J, Tang BW, Nimni ME. Proanthocyanidin: a natural crosslinking reagent for stabilizing collagen matrices. J Biomed Mater Res A. 2003;65A:118–24.

    Article  CAS  Google Scholar 

  22. Duisberg PC, Shires LB, Botkin CW. Determination of Nordihydroguaiaretic acid in leaf of Larrea divaricata (Creosote Bush). Anal Chem. 1949;21:1393–6.

    Article  CAS  Google Scholar 

  23. Chang Y, Hsu CK, Wei HJ, Chen SC, Liang HC, Lai PH, et al. Cell-free xenogenic vascular grafts fixed with glutaraldehyde or genipin: in vitro and in vivo studies. J Biotechnol. 2005;120:207–19.

    Article  CAS  PubMed  Google Scholar 

  24. Flanagan TC, Wilkins B, Black A, Jockenhoevel S, Smith TJ, Pandit AS. A collagen-glycosaminoglycan co-culture model for heart valve tissue engineering applications. Biomaterials. 2006;27:2233–46.

    Article  CAS  PubMed  Google Scholar 

  25. Fischer D, Li Y, Ahlemeyer B, Krieglstein J, Kissel T. In vitro cytotoxicity testing of polycations: influence of polymer structure on cell viability and hemolysis. Biomaterials. 2003;24:1121–31.

    Article  CAS  PubMed  Google Scholar 

  26. Brody S, McMahon J, Yao L, O’Brien M, Dockery P, Pandit A. The effect of cholecyst-derived extracellular matrix on the phenotypic behaviour of valvular endothelial and valvular interstitial cells. Biomaterials. 2007;28:1461–9.

    Article  CAS  PubMed  Google Scholar 

  27. Migneco F, Hollister SJ, Birla RK. Tissue-engineered heart valve prostheses: ‘state of the heart’. Regen Med. 2008;3:399–410.

    Article  CAS  PubMed  Google Scholar 

  28. Badylak SF, Freytes DO, Gilbert TW. Extracellular matrix as a biological scaffold material: Structure and function. Acta Biomater. 2009;5:1–13.

    Article  CAS  PubMed  Google Scholar 

  29. Chaudhry B, Ashton H, Muhamed A, Yost M, Bull S, Frankel D. Nanoscale viscoelastic properties of an aligned collagen scaffold. J Mater Sci Mater Med. 2009;20:257–63.

    Article  CAS  PubMed  Google Scholar 

  30. Tudorache I, Cebotari S, Sturz G, Kirsch L, Hurschler C, Hilfiker A, et al. Tissue engineering of heart valves: biomechanical and morphological properties of decellularized heart valves. J Heart Valve Dis. 2007;16:567–74.

    PubMed  Google Scholar 

  31. Silva RM, Silva GA, Coutinho OP, Mano JF, Reis RL. Preparation and characterisation in simulated body conditions of glutaraldehyde crosslinked chitosan membranes. J Mater Sci Mater Med. 2004;15:1105–12.

    Article  CAS  PubMed  Google Scholar 

  32. Sung HW, Chang Y, Liang IL, Chang WH, Chen YC. Fixation of biological tissues with a naturally occurring crosslinking agent: fixation rate and effects of pH, temperature, and initial fixative concentration. J Biomed Mater Res. 2000;52:77–87.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Life Science, East China Normal University, 3663 Zhongshanbei Road, Shanghai, 200062, People’s Republic of China

    Xiqin Lü & Hongfeng Zhang

  2. State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Dingxi Road, Shanghai, 200050, People’s Republic of China

    Wanyin Zhai, Yanling Zhou & Jiang Chang

  3. Med-X Research Institute of Shanghai Jiaotong University, Shanghai, 200030, People’s Republic of China

    Yue Zhou & Jiang Chang

Authors
  1. Xiqin Lü
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wanyin Zhai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yanling Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yue Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hongfeng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jiang Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hongfeng Zhang or Jiang Chang.

Additional information

Xiqin Lü and Wanyin Zhai contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lü, X., Zhai, W., Zhou, Y. et al. Crosslinking effect of Nordihydroguaiaretic acid (NDGA) on decellularized heart valve scaffold for tissue engineering. J Mater Sci: Mater Med 21, 473–480 (2010). https://doi.org/10.1007/s10856-009-3924-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10856-009-3924-9

Keywords

Search

Navigation