Journal of Materials Science

, Volume 51, Issue 2, pp 1107–1120 | Cite as

Relating ion release and pH to in vitro cell viability for gallium-inclusive bioactive glasses

  • Timothy J. Keenan
  • L. M. Placek
  • T. L. McGinnity
  • M. R. Towler
  • M. M. Hall
  • A. W. Wren
Original Paper


A bioactive glass (BG) in which Ga was substituted for Zn was formulated to investigate whether the ionic form of Ga can elicit effects similar to gallium nitrate. The ion release and pH of BG extracts were evaluated, as well as the in vitro cytocompatibility of extracts in contact with mouse fibroblasts and human osteoblasts. After incubation times of 1 year, the glass (TGa-1) containing the smaller Ga-addition (8 mol%) released the most sodium (Na) (1420 mg/L), silicon (Si) (221 mg/L), and Ga (1295 mg/L), while the glass (TGa-2) containing the larger Ga-addition (16 mol%), exhibited release levels between TGa-1, and the 0 mol% Ga (Control) glass. The pH of all 3 glass extracts steadily increased over time, with maximums observed after 365 days for Control (10.0), TGa-1 (12.2), and TGa-2 (9.7). Cell viability analysis suggested that Ga-release produced toxic effects in L-929 fibroblasts, with less than 3 % viability for both TGa-1 and TGa-2 extracts after 90, 180, and 365 days; however, no significant decrease in MC-3T3 osteoblast viability was observed for TGa-1 extracts after any time period, despite the higher ion release and pH values, and a significant decrease to 51 % viability was only observed for TGa-2 extracts after 365 days. These results suggest that tailoring the release of Ga from BG is not only possible, but also beneficial to the host, thus rendering such glasses useful in bone void-filling applications.


Simulated Body Fluid Bioactive Glass Glass Network Cell Viability Analysis Differential Thermal Analysis Result 
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.


  1. 1.
    Yamamuro T, Hench LL, Wilson J (1990) CRC handbook of bioactive ceramics: calcium phosphate and hydroxylapatite ceramics. CRC Press, Boca RatonGoogle Scholar
  2. 2.
    Hench L (2006) The story of Bioglass®. J Mater Sci Mater Med 17(11):967–978CrossRefGoogle Scholar
  3. 3.
    Ratner BD (2004) Biomaterials science: an introduction to materials in medicine. Academic press, San DiegoGoogle Scholar
  4. 4.
    Hench LL (2009) Genetic design of bioactive glass. J Eur Ceram Soc 29(7):1257–1265CrossRefGoogle Scholar
  5. 5.
    Holloway W, Collier F, Herbst R, Hodge J, Nicholson G (1996) Osteoblast-mediated effects of zinc on isolated rat osteoclasts: inhibition of bone resorption and enhancement of osteoclast number. Bone 19(2):137–142CrossRefGoogle Scholar
  6. 6.
    Yamaguchi M, Mochizuki A, Okada S (1982) Stimulatory effect of zinc on bone growth in weanling rats. J Pharmacobiodyn 5(8):619–626CrossRefGoogle Scholar
  7. 7.
    Peters W, Jackson R, Iwano K, Smith D (1972) The biological response to zinc polyacrylate cement. Clin Orthop Relat Res 88:228–233CrossRefGoogle Scholar
  8. 8.
    Deliormanlı AM (2015) Synthesis and characterization of cerium-and gallium-containing borate bioactive glass scaffolds for bone tissue engineering. J Mater Sci Mater Med 26(2):1–13Google Scholar
  9. 9.
    Shruti S, Salinas AJ, Malavasi G, Lusvardi G, Menabue L, Ferrara C, Mustarelli P, Vallet-Regì M (2012) Structural and in vitro study of cerium, gallium and zinc containing sol–gel bioactive glasses. J Mater Chem 22(27):13698–13706CrossRefGoogle Scholar
  10. 10.
    Salinas A, Shruti S, Malavasi G, Menabue L, Vallet-Regi M (2011) Substitutions of cerium, gallium and zinc in ordered mesoporous bioactive glasses. Acta Biomater 7(9):3452–3458CrossRefGoogle Scholar
  11. 11.
    Hart MM, Adamson RH (1971) Antitumor activity and toxicity of salts of inorganic group IIIa metals: aluminum, gallium, indium, and thallium. Proc Natl Acad Sci 68(7):1623–1626CrossRefGoogle Scholar
  12. 12.
    Warrell RP, Coonley CJ, Straus DJ, Young CW (1983) Treatment of patients with advanced malignant lymphoma using gallium nitrate administered as a seven-day continuous infusion. Cancer 51(11):1982–1987CrossRefGoogle Scholar
  13. 13.
    Pro B, Bociek R, Chitambar CR, Gregory SA, Leonard JP, Smith S, Novick S (2004) Phase 2 multicenter trial of gallium nitrate in patients with advanced non-Hodgkin’s lymphoma (Nhl). vol 104, p 2487Google Scholar
  14. 14.
    Warrell RP Jr, Danieu L, Coonley CJ, Atkins C (1987) Salvage chemotherapy of advanced lymphoma with investigational drugs: mitoguazone, gallium nitrate, and etoposide. Cancer Treat Rep 71(1):47–51Google Scholar
  15. 15.
    Chitambar CR, Zahir SA, Ritch PS, Anderson T (1997) Evaluation of continuous-infusion gallium nitrate and hydroxyurea in combination for the treatment of refractory non-Hodgkin’s lymphoma. Am J Clin Oncol 20(2):173–178CrossRefGoogle Scholar
  16. 16.
    Smith S, Wren K, Stiff P, Toor A, Rodriguez T, van Gestel D (2007) Gallium, rituximab, and dexamethasone for relapsed Nhl. vol 25, p 8079Google Scholar
  17. 17.
    Crawford ED, Saiers JH, Baker LH, Costanzi JH, Bukowski RM (1991) Gallium nitrate in advanced bladder carcinoma: southwest oncology group study. Urology 38(4):355–357CrossRefGoogle Scholar
  18. 18.
    Seligman PA, Crawford ED (1991) Treatment of advanced transitional cell carcinoma of the bladder with continuous-infusion gallium nitrate. J Natl Cancer Inst 83(21):1582–1584CrossRefGoogle Scholar
  19. 19.
    McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Heineman M, Hirsch J, Kelly WK, Scher HI, Bajorin DF (1997) Phase II randomized trial of gallium nitrate plus fluorouracil versus methotrexate, vinblastine, doxorubicin, and cisplatin in patients with advanced transitional-cell carcinoma. J Clin Oncol 15(6):2449–2455Google Scholar
  20. 20.
    Einhorn LH, Roth BJ, Ansari R, Dreicer R, Gonin R, Loehrer PJ (1994) Phase II trial of vinblastine, ifosfamide, and gallium combination chemotherapy in metastatic urothelial carcinoma. J Clin Oncol 12(11):2271–2276Google Scholar
  21. 21.
    Straus DJ “Gallium Nitrate in the Treatment of Lymphoma”; p 25–33 in Vol 30Google Scholar
  22. 22.
    Cvitkovic F, Armand J-P, Tubiana-Hulin M, Rossi J-F, Warrell RP Jr (2006) Randomized, double-blind, phase II trial of gallium nitrate compared with pamidronate for acute control of cancer-related hypercalcemia. Cancer J 12(1):47–53CrossRefGoogle Scholar
  23. 23.
    Warrell R, Murphy W, Schulman P, O’Dwyer P, Heller G (1991) A randomized double-blind study of gallium nitrate compared with etidronate for acute control of cancer-related hypercalcemia. J Clin Oncol 9(8):1467–1475Google Scholar
  24. 24.
    Warrell RP, Israel R, Frisone M, Snyder T, Gaynor JJ, Bockman RS (1988) Gallium nitrate for acute treatment of cancer-related hypercalcemia: a randomized, double-blind comparison to calcitonin. Ann Intern Med 108(5):669–674CrossRefGoogle Scholar
  25. 25.
    Warrell R, Alcock NW, Bockman RS (1987) Gallium nitrate inhibits accelerated bone turnover in patients with bone metastases. J Clin Oncol 5(2):292–298Google Scholar
  26. 26.
    Wren A, Keenan T, Coughlan A, Laffir F, Boyd D, Towler M, Hall M (2013) Characterisation of Ga2O3–Na2O–CaO–ZnO–SiO2 bioactive glasses. J Mater Sci 48(11):3999–4007. doi: 10.1007/s10853-013-7211-2 CrossRefGoogle Scholar
  27. 27.
    Baker DR (1995) Diffusion of silicon and gallium (as an analogue for aluminum) network-forming cations and their relationship to viscosity in albite melt. Geochim Cosmochim Acta 59(17):3561–3571CrossRefGoogle Scholar
  28. 28.
    Kokubo T, Kushitani H, Ohtsuki C, Sakka S, Yamamuro T (1992) Chemical reaction of bioactive glass and glass-ceramics with a simulated body fluid. J Mater Sci Mater Med 3(2):79–83CrossRefGoogle Scholar
  29. 29.
    International Standard 10993-5 “Biological evaluation of medical devices part 5: tests for in vitro cytotoxicity”, Case Postale 56 [CH-1211] (1999)Google Scholar
  30. 30.
    Gandolfi MG, Taddei P, Tinti A, Dorigo EDS, Rossi PL, Prati C (2010) Kinetics of apatite formation on a calcium-silicate cement for root-end filling during ageing in physiological-like phosphate solutions. Clin Oral Invest 14(6):659–668CrossRefGoogle Scholar
  31. 31.
    Boyd D, Towler M, Wren A, Clarkin O (2008) Comparison of an experimental bone cement with surgical Simplex® P, Spineplex® and Cortoss®. J Mater Sci Mater Med 19(4):1745–1752CrossRefGoogle Scholar
  32. 32.
    Gross UM, Strunz V (1980) The anchoring of glass ceramics of different solubility in the femur of the rat. J Biomed Mater Res 14(5):607–618CrossRefGoogle Scholar
  33. 33.
    Ahmed I, Lewis M, Olsen I, Knowles J (2004) Phosphate glasses for tissue engineering: part 2. processing and characterisation of a ternary-based P2O5–CaO–Na2O glass fibre system. Biomaterials 25(3):501–507CrossRefGoogle Scholar
  34. 34.
    Hill R (1996) An alternative view of the degradation of bioglass. J Mater Sci Lett 15(13):1122–1125CrossRefGoogle Scholar
  35. 35.
    Oliveira J, Correia R, Fernandes M (2002) Effects of Si speciation on the in vitro bioactivity of glasses. Biomaterials 23(2):371–379CrossRefGoogle Scholar
  36. 36.
    Cerruti M, Greenspan D, Powers K (2005) Effect of Ph and ionic strength on the reactivity of Bioglass® 45s5. Biomaterials 26(14):1665–1674CrossRefGoogle Scholar
  37. 37.
    Schedle A, Samorapoompichit P, Rausch-Fan X, Franz A, Füreder W, Sperr W, Sperr W, Ellinger A, Slavicek R, Boltz-Nitulescu G (1995) Response of L-929 fibroblasts, human gingival fibroblasts, and human tissue mast cells to various metal cations. J Dent Res 74(8):1513–1520CrossRefGoogle Scholar
  38. 38.
    Li J, Eastman A (1995) Apoptosis in an interleukin-2-dependent cytotoxic T lymphocyte cell line is associated with intracellular acidification role of the Na/H-antiport. J Biol Chem 270(7):3203–3211CrossRefGoogle Scholar
  39. 39.
    Furlong IJ, Ascaso R, Rivas AL, Collins M (1997) Intracellular acidification induces apoptosis by stimulating ice-like protease activity. J Cell Sci 110(5):653–661Google Scholar
  40. 40.
    Kaysinger KK, Ramp WK (1998) Extracellular pH modulates the activity of cultured human osteoblasts. J Cell Biochem 68(1):83–89CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Timothy J. Keenan
    • 1
  • L. M. Placek
    • 1
  • T. L. McGinnity
    • 1
  • M. R. Towler
    • 2
    • 3
  • M. M. Hall
    • 1
  • A. W. Wren
    • 1
  1. 1.Inamori School of EngineeringAlfred UniversityAlfredUSA
  2. 2.Mechanical and Industrial EngineeringRyerson UniversityTorontoCanada
  3. 3.Department of Biomedical EngineeringUniversity MalayaKuala LumpurMalaysia

Personalised recommendations