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Conceptual Study for Tissue-Regenerative Biodegradable Magnesium Implant Integrated with Nitric Oxide-Releasing Nanofibers

  • Jin-Kyung Jeon
  • Hyunseon Seo
  • Jimin Park
  • Soo Ji Son
  • Yeong Rim Kim
  • Eun Shil Kim
  • Jong Woong Park
  • Woong-Gyo Jung
  • Hojeong Jeon
  • Yu-Chan Kim
  • Hyun-Kwang Seok
  • Jae Ho ShinEmail author
  • Myoung-Ryul OkEmail author
Article
  • 32 Downloads

Abstract

The excessive initial corrosion rate of Mg is a critical limitation in the clinical application of biodegradable Mg implants because the device loses its fixation strength before the fractured bone heals. This study suggests a new approach to overcome this hurdle by accelerating tissue regeneration instead of delaying the implant biodegradation. As angiogenesis is an essential process in early bone regeneration, a Mg implant coated with electrospun nanofibers containing nitric oxide (NO), which physiologically promotes angiogenesis, is designed. The integrated device enables adjustable amounts of NO to be stored on the NO donor-conjugated nanofiber coating, stably delivered, and released to the fractured bone tissue near the implanted sites. An in vitro corrosion test reveals no adverse effect of the released NO on the corrosion behavior of the Mg implant. Simultaneously, the optimal concentration level of NO released from the implant significantly enhances tube network formation of human umbilical vein endothelial cells without any cytotoxicity problem. This indicates that angiogenesis can be accelerated by combining NO-releasing nanofibers with a Mg implant. With its proven feasibility, the proposed approach could be a novel solution for the initial stability problem of biodegradable Mg implants, leading to successful bone fixation.

Keywords

Nitric oxide Nanofiber Angiogenesis Biodegradable magnesium implant Bone regeneration 

Notes

Acknowledgements

This research was supported by a grant of the Ministry of Commerce, Industry, and Energy of the Korean Government (Project Number: 10065241) and a grant from the Korea Institute of Science and Technology (2V05460, KIST-Korea University TRC program). This research was also supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Minister of Science, ICT & Future Planning (NRF-2015M3A9E2029186).

References

  1. 1.
    Q. Chen, G.A. Thouas, Metallic implant biomaterials. Mater. Sci. Eng. R 87, 1–57 (2015)CrossRefGoogle Scholar
  2. 2.
    X.N. Gu, S.S. Li, X.M. Li, Y.B. Fan, Magnesium based degradable biomaterials: a review. Front. Mater. Sci. 8, 200–218 (2014)CrossRefGoogle Scholar
  3. 3.
    F. Witte, V. Kaese, H. Haferkamp, E. Switzer, A. Meyer-Lindenberg, C. Wirth, H. Windhagen, In vivo corrosion of four magnesium alloys and the associated bone response. Biomaterials 26, 3557–3563 (2005)CrossRefGoogle Scholar
  4. 4.
    M.P. Staiger, A.M. Pietak, J. Huadmai, G. Dias, Magnesium and its alloys as orthopedic biomaterials: a review. Biomaterials 27, 1728–1734 (2006)CrossRefGoogle Scholar
  5. 5.
    M. Salahshoor, Y. Guo, Biodegradable orthopedic magnesium-calcium (MgCa) alloys, processing, and corrosion performance. Materials 5, 135–155 (2012)CrossRefGoogle Scholar
  6. 6.
    H. Waizy, J.-M. Seitz, J. Reifenrath, A. Weizbauer, F.-W. Bach, A. Meyer-Lindenberg, B. Denkena, H. Windhagen, Biodegradable magnesium implants for orthopedic applications. J. Mater. Sci. 48, 39–50 (2013)CrossRefGoogle Scholar
  7. 7.
    A. Atrens, M. Liu, N.I.Z. Abidin, Corrosion mechanism applicable to biodegradable magnesium implants. Mater. Sci. Eng. B 176, 1609–1636 (2011)CrossRefGoogle Scholar
  8. 8.
    J.-W. Lee, H.-S. Han, K.-J. Han, J. Park, H. Jeon, M.-R. Ok, H.-K. Seok, J.-P. Ahn, K.E. Lee, D.-H. Lee, S.J. Yang, S.Y. Cho, P.R. Cha, H. Kwon, T.H. Nam, J.H. Han, H.J. Rho, K.S. Lee, Y.C. Kim, D. Mantovani, Long-term clinical study and multiscale analysis of in vivo biodegradation mechanism of Mg alloy. Proc. Natl. Acad. Sci. USA 113, 716–721 (2016)CrossRefGoogle Scholar
  9. 9.
    G. Song, Control of biodegradation of biocompatable magnesium alloys. Corros. Sci. 49, 1696–1701 (2007)CrossRefGoogle Scholar
  10. 10.
    T. Karus, S.F. Fischerauer, A.C. Hänzi, P.J. Uggowitzer, J.F. Löffler, A.M. Weinberg, Magnesium alloys for temporary implants in osteosynthesis: in vivo studies of their degradation and interaction with bone. Acta Biomater. 8, 1230–1238 (2012)CrossRefGoogle Scholar
  11. 11.
    S. Yoshizawa, A. Brown, A. Barchowsky, C. Sfeir, Magnesium ion stimulation of bone marrow stromal cells enhances osteogenic activity, simulating the effect of magnesium alloy degradation. Acta Biomater. 10, 2834–2842 (2014)CrossRefGoogle Scholar
  12. 12.
    J. Vormann, Magnesium: nutrition and metabolism. Mol. Aspects Med. 24, 27–37 (2003)CrossRefGoogle Scholar
  13. 13.
    H. Zreiqat, C. Howlett, A. Zannettino, P. Evans, G. Schulze-Tanzil, C. Knabe, M. Shakibaei, Mechanisms of magnesium-stimulated adhesion of osteoblastic cells to commonly used orthopaedic implants. J. Biomed. Mater. Res. Part A 62, 175–184 (2002)CrossRefGoogle Scholar
  14. 14.
    Y. Yamasaki, Y. Yoshida, M. Okazaki, A. Shimazu, T. Uchida, T. Kubo, Y. Akagawa, Y. Hamada, J. Takahashi, N. Matsuura, Synthesis of functionally graded MgCO3 apatite accelerating osteoblast adhesion. J. Biomed. Mater. Res. Part A 62, 99–105 (2002)CrossRefGoogle Scholar
  15. 15.
    G.L. Song, A.A. Atrens, Corrosion mechanisms of magnesium alloys. Adv. Eng. Mater. 1, 11–33 (1999)CrossRefGoogle Scholar
  16. 16.
    P.R. Cha, H.S. Han, G.F. Yang, Y.C. Kim, K.H. Hong, S.C. Lee, J.Y. Jung, J.P. Ahn, Y.Y. Kim, S.Y. Cho, J.Y. Byun, K.S. Lee, S.J. Yang, H.K. Seok, Biodegradability engineering of biodegradable Mg alloys: tailoring the electrochemical properties and microstructure of constituent phases. Sci. Rep. 3, 2367 (2013).  https://doi.org/10.1038/srep02367 CrossRefGoogle Scholar
  17. 17.
    G.F. Yang, Y.C. Kim, H.S. Han, G.C. Lee, H.K. Seok, J.C. Lee, In vitro dynamic degradation behavior of new magnesium alloy for orthopedic applications. J. Biomed. Mater. Res. Part B 103, 807 (2015)CrossRefGoogle Scholar
  18. 18.
    R.A. Carano, E.H. Filvaroff, Angiogenesis and bone repair. Drug Discov. Today 8, 980–989 (2003)CrossRefGoogle Scholar
  19. 19.
    H.-P. Gerber, T.H. Vu, A.M. Ryan, J. Kowalski, Z. Werb, N. Ferrara, VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat. Med. 5, 623–628 (1999)CrossRefGoogle Scholar
  20. 20.
    J. Street, M. Bao, S. Bunting, F.V. Peale, N. Ferrara, H. Steinmetz, J. Hoeffel, J.L. Cleland, A. Daugherty, N. van Bruggen, Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc. Natl. Acad. Sci. USA 99, 9656–9661 (2002)CrossRefGoogle Scholar
  21. 21.
    J. Kanczler, R. Oreffo, Osteogenesis and angiogenesis: the potential for engineering bone. Eur. Cells Mater. 15, 100–114 (2008)CrossRefGoogle Scholar
  22. 22.
    T.D. Fang, A. Salim, W. Xia, R.P. Nacamuli, S. Guccione, H.M. Song, R.A. Carano, E.H. Filvaroff, M.D. Bednarski, A.J. Giaccia, Angiogenesis is required for successful bone induction during distraction osteogenesis. J. Bone Miner. Res. 20, 1114–1124 (2005)CrossRefGoogle Scholar
  23. 23.
    A.W. Carpenter, M.H. Schoenfisch, Nitric oxide release: part II. Therapeutic applications. Chem. Soc. Rev. 41, 3742–3752 (2012)CrossRefGoogle Scholar
  24. 24.
    P.D. Ray, B.-W. Huang, Y. Tsuji, Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell. Signal. 24, 981–990 (2012)CrossRefGoogle Scholar
  25. 25.
    B.C. Dickinson, C.J. Chang, Chemistry and biology of reactive oxygen species in signaling or stress responses. Nat. Chem. Biol. 7, 504–511 (2011)CrossRefGoogle Scholar
  26. 26.
    C.C. Winterbourn, Reconciling the chemistry and biology of reactive oxygen species. Nat. Chem. Biol. 4, 278–286 (2008)CrossRefGoogle Scholar
  27. 27.
    T. Finkel, Signal transduction by reactive oxygen species. J. Cell Biol. 194, 7–15 (2011)CrossRefGoogle Scholar
  28. 28.
    C. Xia, Q. Meng, L.-Z. Liu, Y. Rojanasakul, X.-R. Wang, B.-H. Jiang, Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor. Cancer Res. 67, 10823–10830 (2007)CrossRefGoogle Scholar
  29. 29.
    R. Zhang, L. Wang, L. Zhang, J. Chen, Z. Zhu, Z. Zhang, M. Chopp, Nitric oxide enhances angiogenesis via the synthesis of vascular endothelial growth factor and cGMP after stroke in the rat. Circ. Res. 92, 308–313 (2003)CrossRefGoogle Scholar
  30. 30.
    A. Papapetropoulos, G. García-Cardeña, J.A. Madri, W.C. Sessa, Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells. J. Clin. Investig. 100, 3131–3139 (1997)CrossRefGoogle Scholar
  31. 31.
    A.D. Diwan, M.X. Wang, D. Jang, W. Zhu, G.A. Murrell, Nitric oxide modulates fracture healing. J. Bone Miner. Res. 15, 342–351 (2000)CrossRefGoogle Scholar
  32. 32.
    J.H. Shin, S.K. Metzger, M.H. Schoenfisch, Synthesis of nitric oxide-releasing silica nanoparticles. J. Am. Chem. Soc. 129, 4612–4619 (2007)CrossRefGoogle Scholar
  33. 33.
    M.E. Robbins, E.D. Hopper, M.H. Schoenfisch, Synthesis and characterization of nitric oxide-releasing sol–gel microarrays. Langmuir 20, 10296–10302 (2004)CrossRefGoogle Scholar
  34. 34.
    M. Miller, I. Megson, Recent developments in nitric oxide donor drugs. Br. J. Pharmacol. 151, 305–321 (2007)CrossRefGoogle Scholar
  35. 35.
    W. He, H.-K. Kim, W.G. Wamer, D. Melka, J.H. Callahan, J.-J. Yin, Photogenerated charge carriers and reactive oxygen species in ZnO/Au hybrid nanostructures with enhanced photocatalytic and antibacterial activity. J. Am. Chem. Soc. 136, 750–757 (2013)CrossRefGoogle Scholar
  36. 36.
    J. Macak, F. Schmidt-Stein, P. Schmuki, Efficient oxygen reduction on layers of ordered TiO2 nanotubes loaded with Au nanoparticles. Electrochem. Commun. 9, 1783–1787 (2007)CrossRefGoogle Scholar
  37. 37.
    Y. Li, W. Zhang, J. Niu, Y. Chen, Mechanism of photogenerated reactive oxygen species and correlation with the antibacterial properties of engineered metal-oxide nanoparticles. ACS Nano 6, 5164–5173 (2012)CrossRefGoogle Scholar
  38. 38.
    J. Park, P. Du, J.K. Jeon, G.H. Jang, M.P. Hwang, H.S. Han, K. Park, K.H. Lee, J.W. Lee, H. Jeon, Y.C. Kim, J.W. Park, H.K. Seok, M.-R. Ok, Magnesium corrosion triggered spontaneous generation of H2O2 on oxidized titanium for promoting angiogenesis. Angew. Chem. Int. Ed. Engl. 54, 14753–14757 (2015)CrossRefGoogle Scholar
  39. 39.
    S.M. Marxer, A.R. Rothrock, B.J. Nablo, M.E. Robbins, M.H. Schoenfisch, Preparation of nitric oxide (NO)-releasing sol–gels for biomaterial applications. Chem. Mater. 15, 4193–4199 (2003)CrossRefGoogle Scholar
  40. 40.
    D.A. Riccio, M.H. Schoenfisch, Nitric oxide release: part I. Macromolecular scaffolds. Chem. Soc. Rev. 41, 3731–3741 (2012)CrossRefGoogle Scholar
  41. 41.
    J. Saraiva, S.S. Marotta-Oliveira, S.A. Cicillini, J.D.O. Eloy, J.M. Marchetti, Nanocarriers for nitric oxide delivery. J. Drug Deliv. 2011, 936438 (2011)CrossRefGoogle Scholar
  42. 42.
    T.P. Misko, R. Schilling, D. Salvemini, W. Moore, M. Currie, A fluorometric assay for the measurement of nitrite in biological samples. Anal. Biochem. 214, 11–16 (1993)CrossRefGoogle Scholar
  43. 43.
    R.J. Holland, J.R. Klose, J.R. Deschamps, Z. Cao, L.K. Keefer, J.E. Saavedra, Direct reaction of amides with nitric oxide to form diazeniumdiolates. J. Org. Chem. 79, 9389–9393 (2014)CrossRefGoogle Scholar
  44. 44.
    J.A. Maier, D. Bernardini, Y. Rayssiguier, A. Mazur, High concentrations of magnesium modulate vascular endothelial cell behaviour in vitro. Biochim. Biophys. Acta Mol. Basis Dis. 1689, 6–12 (2004)CrossRefGoogle Scholar
  45. 45.
    M. Shechter, M. Sharir, M.J.P. Labrador, J. Forrester, B. Silver, C.N.B. Merz, Oral magnesium therapy improves endothelial function in patients with coronary artery disease. Circulation 102, 2353–2358 (2000)CrossRefGoogle Scholar

Copyright information

© The Korean Institute of Metals and Materials 2019

Authors and Affiliations

  • Jin-Kyung Jeon
    • 1
  • Hyunseon Seo
    • 1
  • Jimin Park
    • 1
    • 2
  • Soo Ji Son
    • 3
  • Yeong Rim Kim
    • 4
  • Eun Shil Kim
    • 1
  • Jong Woong Park
    • 5
  • Woong-Gyo Jung
    • 5
  • Hojeong Jeon
    • 1
    • 6
  • Yu-Chan Kim
    • 1
  • Hyun-Kwang Seok
    • 1
    • 6
  • Jae Ho Shin
    • 3
    • 4
    Email author
  • Myoung-Ryul Ok
    • 1
    Email author return OK on get
  1. 1.Center for BiomaterialsKorea Institute of Science and Technology (KIST)SeoulRepublic of Korea
  2. 2.Department of Material Science and EngineeringMassachusetts Institute of TechnologyCambridgeUSA
  3. 3.Department of ChemistryKwangwoon UniversitySeoulRepublic of Korea
  4. 4.Medical Sensor Biomaterial Research CenterKwangwoon UniversitySeoulRepublic of Korea
  5. 5.Department of Orthopedic Surgery, School of MedicineKorea UniversitySeoulRepublic of Korea
  6. 6.Division of Bio-Medical Science and Technology, KIST SchoolKorea University of Science and TechnologySeoulRepublic of Korea

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