Journal of Materials Science

, Volume 52, Issue 15, pp 8785–8792 | Cite as

Angiogenic potential of boron-containing bioactive glasses: in vitro study

  • P. Balasubramanian
  • L. Hupa
  • B. Jokic
  • R. Detsch
  • A. Grünewald
  • Aldo R. BoccacciniEmail author
In Honor of Larry Hench


Boron-containing bioactive glasses (BGs) are being extensively researched for the treatment and regeneration of bone defects because of their osteostimulatory and neovascularization potential. In this study, we report the effects of the ionic dissolution products (IDPs) of different boron-doped, borosilicate, and borate BG scaffolds on mouse bone marrow stromal cells in vitro, using an angiogenesis assay. Five different BG scaffolds of the system SiO2–Na2O–K2O–MgO–CaO–P2O5–B2O3 (with varying amounts of SiO2 and B2O3) were fabricated by the foam replication technique. Bone marrow stromal cells were cultivated in contact with the IDPs of the boron-containing BG scaffolds at different concentrations for 48 h. The expression and secretion of vascular endothelial growth factor (VEGF) from the cultured cells was measured quantitatively using the VEGF ELISA Kit. Cell viability and cell morphology were determined using WST-8 assay and H&E staining, respectively. The cellular response was found to be dependent on boron content and the B release profile from the glasses corresponded to the positive or negative biological activity of the BGs.


Vascular Endothelial Growth Factor Bone Marrow Stromal Cell Vascular Endothelial Growth Factor Concentration Vascular Endothelial Growth Factor Secretion Vascular Endothelial Growth Factor Release 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors acknowledge European Commission funding under the 7th Framework Programme (Marie Curie Initial Training Networks; Grant No. 289958, Bioceramics for bone repair).


  1. 1.
    Lovett M, Lee K, Edwards A, Kaplan DL (2009) Vascularization strategies for tissue engineering. Tissue Eng Part B 15:353–370. doi: 10.1089/ten.teb.2009.0085 CrossRefGoogle Scholar
  2. 2.
    Kanczler JM, Oreffo RO (2008) Osteogenesis and angiogenesis: the potential for engineering bone. Eur Cell Mater 15:100–114CrossRefGoogle Scholar
  3. 3.
    Trueta J (1964) The role of the vessels in osteogenesis. Plast Reconstr Surg 33:206. doi: 10.1097/00006534-196402000-00034 CrossRefGoogle Scholar
  4. 4.
    Tatsuyama K, Maezawa Y, Baba H et al (2000) Expression of various growth factors for cell proliferation and cytodifferentiation during fracture repair of bone. Eur J Histochem 44:269–278Google Scholar
  5. 5.
    Gerstenfeld LC, Cullinane DM, Barnes GL et al (2003) Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation. J Cell Biochem 88:873–884. doi: 10.1002/jcb.10435 CrossRefGoogle Scholar
  6. 6.
    Friedenstein AJ, Chailakhjan RK, Lalykina KS (1970) The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet 3:393–403. doi: 10.1111/j.1365-2184.1970.tb00347.x Google Scholar
  7. 7.
    Horwitz EM, Keating A (2000) Nonhematopoietic mesenchymal stem cells: what are they? Cytotherapy 2:387–388. doi: 10.1080/146532400539305 CrossRefGoogle Scholar
  8. 8.
    Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP (1968) Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 6:230–247. doi: 10.1097/00007890-196803000-00009 CrossRefGoogle Scholar
  9. 9.
    Friedenstein AJ, Deriglasova UF, Kulagina NN et al (1974) Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp Hematol 2:83–92. doi: 10.1016/j.exphem.2005.10.008 Google Scholar
  10. 10.
    Coultas L, Chawengsaksophak K, Rossant J (2005) Endothelial cells and VEGF in vascular development. Nature 438:937–945. doi: 10.1038/nature04479 CrossRefGoogle Scholar
  11. 11.
    Laschke MW, Harder Y, Amon M et al (2006) Angiogenesis in tissue engineering: breathing life into constructed tissue substitutes. Tissue Eng 12:2093–2104. doi: 10.1089/ten.2006.12.ft-130 CrossRefGoogle Scholar
  12. 12.
    Gorustovich AA, Roether JA, Boccaccini AR (2010) Effect of bioactive glasses on angiogenesis: a review of in vitro and in vivo evidences. Tissue Eng Part B 16:199–207. doi: 10.1089/ten.TEB.2009.0416 CrossRefGoogle Scholar
  13. 13.
    Jung SB, Day DE (2013) Wound care. US 8,535,710 B2Google Scholar
  14. 14.
    Jung SB, Day DE (2012) Controlling vessel growth and directionality in mammals and implantable material. US 8,337,875 B2Google Scholar
  15. 15.
    Hoppe A, Mourino V, Boccaccini AR (2013) Therapeutic inorganic ions in bioactive glasses to enhance bone formation and beyond. Biomater Sci 1:254–256. doi: 10.1039/c2bm00116k CrossRefGoogle Scholar
  16. 16.
    Gerhardt LC, Widdows KL, Erol MM et al (2011) The pro-angiogenic properties of multi-functional bioactive glass composite scaffolds. Biomaterials 32:4096–4108. doi: 10.1016/j.biomaterials.2011.02.032 CrossRefGoogle Scholar
  17. 17.
    Detsch R, Stoor P, Grünewald A et al (2014) Increase in VEGF secretion from human fibroblast cells by bioactive glass S53P4 to stimulate angiogenesis in bone. J Biomed Mater Res Part A 102:4055–4061. doi: 10.1002/jbm.a.35069 CrossRefGoogle Scholar
  18. 18.
    Gorustovich AA, Porto López JM, Guglielmotti MB, Cabrini RL (2006) Biological performance of boron-modified bioactive glass particles implanted in rat tibia bone marrow. Biomed Mater 1:100–105. doi: 10.1088/1748-6041/1/3/002 CrossRefGoogle Scholar
  19. 19.
    Haro Durand LA, Vargas GE, Romero NM et al (2015) Angiogenic effects of ionic dissolution products released from a boron-doped 45S5 bioactive glass. J Mater Chem B 3:1142–1148. doi: 10.1039/C4TB01840K CrossRefGoogle Scholar
  20. 20.
    Bi L, Rahaman MN, Day DE et al (2013) Effect of bioactive borate glass microstructure on bone regeneration, angiogenesis, and hydroxyapatite conversion in a rat calvarial defect model. Acta Biomater 9:8015–8026. doi: 10.1016/j.actbio.2013.04.043 CrossRefGoogle Scholar
  21. 21.
    Wang H, Zhao S, Zhou J et al (2014) Evaluation of borate bioactive glass scaffolds as a controlled delivery system for copper ions in stimulating osteogenesis and angiogenesis in bone healing. J Mater Chem B 2:8547–8557. doi: 10.1039/C4TB01355G CrossRefGoogle Scholar
  22. 22.
    Zhao S, Wang H, Zhang Y et al (2015) Copper-doped borosilicate bioactive glass scaffolds with improved angiogenic and osteogenic capacity for repairing osseous defects. Acta Biomater 14:185–196. doi: 10.1016/j.actbio.2014.12.010 CrossRefGoogle Scholar
  23. 23.
    Balasubramanian P, Grünewald A, Detsch R et al (2016) Ion release, hydroxyapatite conversion, and cytotoxicity of boron-containing bioactive glass scaffolds. Int J Appl Glass Sci 10:1–10. doi: 10.1111/ijag.12206 Google Scholar
  24. 24.
    Chen QZ, Thompson ID, Boccaccini AR (2006) 45S5 Bioglass-derived glass-ceramic scaffolds for bone tissue engineering. Biomaterials 27:2414–2425. doi: 10.1016/j.biomaterials.2005.11.025 CrossRefGoogle Scholar
  25. 25.
    Hunziker EB (1994) Mechanism of longitudinal bone growth and its regulation by growth plate chondrocytes. Microsc Res Tech 28:505–519. doi: 10.1002/jemt.1070280606 CrossRefGoogle Scholar
  26. 26.
    Gerber HP, Vu TH, Ryan AM et al (1999) VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med 5:623–628. doi: 10.1038/9467 CrossRefGoogle Scholar
  27. 27.
    Street J, Bao M, DeGuzman L et al (2002) Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci USA 99:9656–9661. doi: 10.1073/pnas.152324099 CrossRefGoogle Scholar
  28. 28.
    Zelzer E, McLean W, Ng Y-S et al (2002) Skeletal defects in VEGF(120/120) mice reveal multiple roles for VEGF in skeletogenesis. Development 129:1893–1904Google Scholar
  29. 29.
    Brown RF, Rahaman MN, Dwilewicz AB et al (2009) Effect of borate glass composition on its conversion to hydroxyapatite and on the proliferation of MC3T3-E1 cells. J Biomed Mater Res Part A 88:392–400. doi: 10.1002/jbm.a.31679 CrossRefGoogle Scholar
  30. 30.
    Hakki SS, Bozkurt BS, Hakki EE (2010) Boron regulates mineralized tissue-associated proteins in osteoblasts (MC3T3-E1). J Trace Elem Med Biol 24:243–250. doi: 10.1016/j.jtemb.2010.03.003 CrossRefGoogle Scholar
  31. 31.
    Haro Durand LA, Góngora A, Porto López JM et al (2014) In vitro endothelial cell response to ionic dissolution products from boron-doped bioactive glass in the SiO2 –CaO–P2O5–Na2O system. J Mater Chem B 2:7620–7630. doi: 10.1039/C4TB01043D CrossRefGoogle Scholar
  32. 32.
    Dzondo-Gadet M, Mayap-Nzietchueng R, Hess K et al (2002) Action of boron at the molecular level: effects on transcription and translation in an acellular system. Biol Trace Elem Res 85:23–33. doi: 10.1385/BTER:85:1:23 CrossRefGoogle Scholar
  33. 33.
    Benderdour M, Hess K, Nabet P et al (1998) Boron modulates extracellular matrix and TNF a synthesis in human fibroblasts. Biochem Biophys Res Commun 751:746–751CrossRefGoogle Scholar
  34. 34.
    Fu Q, Rahaman MN, Bal BS et al (2010) Silicate, borosilicate, and borate bioactive glass scaffolds with controllable degradation rate for bone tissue engineering applications. II. In vitro and in vivo biological evaluation. J Biomed Mater Res A 95:172–179. doi: 10.1002/jbm.a.32823 CrossRefGoogle Scholar
  35. 35.
    Wu C, Miron R, Sculean A et al (2011) Proliferation, differentiation and gene expression of osteoblasts in boron-containing associated with dexamethasone deliver from mesoporous bioactive glass scaffolds. Biomaterials 32:7068–7078. doi: 10.1016/j.biomaterials.2011.06.009 CrossRefGoogle Scholar
  36. 36.
    Park M, Li Q, Shcheynikov N et al (2004) NaBC1 is a ubiquitous electrogenic Na+-coupled borate transporter essential for cellular boron homeostasis and cell growth and proliferation. Mol Cell 16:331–341. doi: 10.1016/j.molcel.2004.09.030 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • P. Balasubramanian
    • 1
  • L. Hupa
    • 2
  • B. Jokic
    • 3
  • R. Detsch
    • 1
  • A. Grünewald
    • 1
  • Aldo R. Boccaccini
    • 1
    Email author
  1. 1.Department of Materials Science and Engineering, Institute of BiomaterialsUniversity of Erlangen-NurembergErlangenGermany
  2. 2.Johan Gadolin Process Chemistry CentreÅbo Akademi UniversityTurkuFinland
  3. 3.Faculty of Technology and MetallurgyUniversity of BelgradeBelgradeSerbia

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