The role of citrate, lactate and transferrin in determining titanium release from surgical devices into human serum

  • Justin P. CurtinEmail author
  • Minji Wang
  • Tianfan Cheng
  • Lijian Jin
  • Hongzhe Sun
Original Paper


The presence of ionic titanium in the serum of patients with titanium implants is currently unexplained. This is presumed due to corrosion, and yet the serum titanium concentration measured in patients is far greater than that predicted by its solubility. The binding of titanium ion as Ti(IV) to human transferrin (hTF) in serum indicates that Ti(IV) ions interact with human physiology. This is an intriguing finding since there is currently no known role for titanium ions in human physiology. Thus, understanding the factors that determine in vivo titanium ion release is relevant to further understanding this metal’s interactions with human biochemistry. The present study sought to determine the extent of titanium ion release of into human serum in vitro, and the role of citrate, lactate and hTF in this process. It was found that, when surgical devices of commercially pure titanium were placed into human serum, citrate and lactate concentrations were the prime determinants of titanium release. Crystallography revealed Ti(IV) bound to hTF in the presence of citrate alone, signalling that citrate can act as an independent ligand for Ti(IV) binding to hTF. Based on these findings, a two-stage process of titanium ion release into human serum that is dependent upon both citrate and hTF is proposed to explain the ongoing presence of titanium ion in human subjects with implanted titanium devices.


Titanium Corrosion Transferrin Citrate Lactate 



Synthes Craniofacial Modular System—AO Foundation




4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid


Human serum


Human serum transferrin


Inductively coupled plasma-optical emission spectroscopy




Poly(ethylene glycol)


Scanning electron microscopy





We thank Prof. Quan Hao (School of Biomedical Sciences, HKU) for help in X-ray diffraction data collection and Shanghai Synchrotron Radiation Facility (Shanghai Institute of Applied Physics, Chinese Academy of Sciences, China PR) and their staff for providing beam-time and the support at the BL17U1 station (SSRF) for their kind help and H. Y. Tong (Dentistry, HKU), C. L. Yu (Dentistry, HKU), Paul K. D. Lee (Dentistry, HKU) and S. W. Lee (Dentistry, HKU) for their help with our experiments. The authors thank the Modern Dental Laboratory/the University of Hong Kong (HKU) Endowment Fund to L.J. Jin and the Research Grants Council of HKSAR and the University of Hong Kong (Seed funding for Basic Research (201504159007)) for support.

Supplementary material

775_2018_1557_MOESM1_ESM.docx (3.1 mb)
Supplementary material 1 (DOCX 3186 kb)


  1. 1.
    Ainouche L, Hamadou L, Kadri A, Benbrahim N, Bradai D (2014) Electrochim Acta 133:597–609CrossRefGoogle Scholar
  2. 2.
    Solar RJ, Pollack SR, Korostoff E (1979) J Biomed Mater Res 13:217–250CrossRefPubMedGoogle Scholar
  3. 3.
    Tengvall P, Lundstrom I (1992) Clin Mater 9:115–134CrossRefPubMedGoogle Scholar
  4. 4.
    West JM (1980) Basic corrosion and oxidation. Halsted Press, ChichesterGoogle Scholar
  5. 5.
    Turner DR, Whitfield M, Dickson AG (1981) Geochim Cosmochim Acta 45:855–881CrossRefGoogle Scholar
  6. 6.
    Woodman JL, Jacobs JJ, Galante JO, Urban RM (1984) J Orthop Res 1:421–430CrossRefPubMedGoogle Scholar
  7. 7.
    Jacobs JJ, Silverton C, Hallab NJ, Skipor AK, Patterson L, Black J, Galante JO (1999) Clin Orthop Relat Res 358:173–180CrossRefGoogle Scholar
  8. 8.
    Levine BR, Hsu AR, Skipor AK, Hallab NJ, Paprosky WG, Galante JO, Jacobs JJ (2013) J Bone Jt Surg Am 95:512–518CrossRefGoogle Scholar
  9. 9.
    Lavigne M, Belzile EL, Roy A, Morin F, Amzica T, Vendittoli PA (2011) J Bone Jt Surg Am 93(Suppl 2):128–136CrossRefGoogle Scholar
  10. 10.
    Jacobs JJ, Skipor AK, Patterson LM, Hallab NJ, Paprosky WG, Black J, Galante JO (1998) J Bone Jt Surg Am 80:1447–1458CrossRefGoogle Scholar
  11. 11.
    Kasai Y, Iida R, Uchida A (2003) Spine (Phila Pa 1976) 28:1320–1326Google Scholar
  12. 12.
    Trinchi V, Nobis M, Cecchele D (1992) Ital J Orthop Traumatol 18:331–339PubMedGoogle Scholar
  13. 13.
    de Morais LS, Serra GG, Albuquerque Palermo EF, Andrade LR, Muller CA, Meyers MA, Elias CN (2009) Am J Orthod Dentofac Orthop 135:522–529CrossRefGoogle Scholar
  14. 14.
    Nuevo-Ordonez Y, Montes-Bayon M, Blanco-Gonzalez E, Paz-Aparicio J, Raimundez JD, Tejerina JM, Pena MA, Sanz-Medel A (2011) Anal Bioanal Chem 401:2747–2754CrossRefPubMedGoogle Scholar
  15. 15.
    Cobelli N, Scharf B, Crisi GM, Hardin J, Santambrogio L (2011) Nat Rev Rheumatol 7:600–608CrossRefPubMedGoogle Scholar
  16. 16.
    Jacobs JJ, Skipor AK, Campbell PA, Hallab NJ, Urban RM, Amstutz HC (2004) J Arthroplasty 19:59–65CrossRefPubMedGoogle Scholar
  17. 17.
    Leopold SS, Berger RA, Patterson L, Skipor AK, Urban RM, Jacobs JJ (2000) J Arthroplasty 15:938–943CrossRefPubMedGoogle Scholar
  18. 18.
    Loza-Rosas SA, Saxena M, Delgado Y, Gaur K, Pandrala M, Tinoco AD (2017) Metallomics 9:346–356CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Cadosch D, Chan E, Gautschi OP, Filgueira L (2009) J Biomed Mater Res Part A 91:1252–1262CrossRefGoogle Scholar
  20. 20.
    Finet B, Weber G, Cloots R (2000) Mater Lett 43:159–165CrossRefGoogle Scholar
  21. 21.
    Franchi M, Orsini E, Martini D, Ottani V, Fini M, Giavaresi G, Giardino R, Ruggeri A (2007) Micron 38:618–625CrossRefPubMedGoogle Scholar
  22. 22.
    Schliephake H, Reiss G, Urban R, Neukam FW, Guckel S (1993) Int J Oral Maxillofac Implants 8:502–511PubMedGoogle Scholar
  23. 23.
    Knauss KG, Dibley MJ, Bourcier WL, Shaw HF (2001) Appl Geochem 16:1115–1128CrossRefGoogle Scholar
  24. 24.
    Schmidt J, Vogelsberger W (2009) J Solut Chem 38:1267–1282CrossRefGoogle Scholar
  25. 25.
    Sugimoto T, Zhou X (2002) J Colloid Interface Sci 252:347–353CrossRefPubMedGoogle Scholar
  26. 26.
    Curtin JP, Wang M (2017) J Biol Inorg Chem 22:799–806CrossRefPubMedGoogle Scholar
  27. 27.
    Hallab NJ, Skipor A, Jacobs JJ (2003) J Biomed Mater Res Part A 65:311–318CrossRefGoogle Scholar
  28. 28.
    Bruneel N, Helsen JA (1988) J Biomed Mater Res 22:203–214CrossRefPubMedGoogle Scholar
  29. 29.
    Strietzel R, Hosch A, Kalbfleisch H, Buch D (1998) Biomaterials 19:1495–1499CrossRefPubMedGoogle Scholar
  30. 30.
    Koike M, Fujii H (2001) Biomaterials 22:2931–2936CrossRefPubMedGoogle Scholar
  31. 31.
    Rykowska I, Makuch K, Wasiak W (2015) Anal Methods 7:9226–9236CrossRefGoogle Scholar
  32. 32.
    Tinoco AD, Eames EV, Valentine AM (2008) J Am Chem Soc 130:2262–2270CrossRefPubMedGoogle Scholar
  33. 33.
    Tinoco AD, Valentine AM (2005) J Am Chem Soc 127:11218–11219CrossRefPubMedGoogle Scholar
  34. 34.
    Nuevo-Ordonez Y, Montes-Bayon M, Blanco Gonzalez E, Sanz-Medel A (2011) Metallomics 3:1297–1303CrossRefPubMedGoogle Scholar
  35. 35.
    Sun HZ, Li HY, Weir RA, Sadler PJ (1998) Angew Chem Int Edit 37:1577–1579CrossRefGoogle Scholar
  36. 36.
    Guo M, Sun H, McArdle HJ, Gambling L, Sadler PJ (2000) Biochemistry 39:10023–10033CrossRefPubMedGoogle Scholar
  37. 37.
    Zierden MR, Valentine AM (2016) Metallomics 8:9–16CrossRefPubMedGoogle Scholar
  38. 38.
    Golasik M, Herman M, Piekoszewski W (2016) Metallomics 8:1227–1242CrossRefPubMedGoogle Scholar
  39. 39.
    Cadosch D, Chan E, Gautschi OP, Meagher J, Zellweger R, Filgueira L (2009) J Biomed Mater Res Part A 91:29–36CrossRefGoogle Scholar
  40. 40.
    Cadosch D, Sutanto M, Chan E, Mhawi A, Gautschi OP, von Katterfeld B, Simmen HP, Filgueira L (2010) J Orthop Res 28:341–347PubMedGoogle Scholar
  41. 41.
    Makihira S, Mine Y, Nikawa H, Shuto T, Iwata S, Hosokawa R, Kamoi K, Okazaki S, Yamaguchi Y (2010) Toxicol In Vitro 24:1905–1910CrossRefPubMedGoogle Scholar
  42. 42.
    Taira M, Sasaki K, Saitoh S, Nezu T, Sasaki M, Kimura S, Terasaki K, Sera K, Narushima T, Araki Y (2006) Dent Mater J 25:726–732CrossRefPubMedGoogle Scholar
  43. 43.
    Chan EP, Mhawi A, Clode P, Saunders M, Filgueira L (2009) Metallomics 1:166–174CrossRefPubMedGoogle Scholar
  44. 44.
    Pettersson M, Kelk P, Belibasakis GN, Bylund D, Molinthoren M, Johansson A (2016) J Periodontal Res. PubMedPubMedCentralGoogle Scholar
  45. 45.
    Thompson GJ, Puleo DA (1995) J Appl Biomater 6:249–258CrossRefPubMedGoogle Scholar
  46. 46.
    Chan E, Cadosch D, Gautschi OP, Sprengel K, Filgueira L (2011) J Appl Biomater Biomech 9:137–143PubMedGoogle Scholar
  47. 47.
    Cadosch D, Gautschi OP, Chan E, Simmen HP, Filgueira L (2010) J Biomed Mater Res Part A 92:475–483Google Scholar
  48. 48.
    Mine Y, Makihira S, Nikawa H, Murata H, Hosokawa R, Hiyama A, Mimura S (2010) J Prosthodont Res 54:1–6CrossRefPubMedGoogle Scholar
  49. 49.
    Valles G, Gil-Garay E, Munuera L, Vilaboa N (2008) Biomaterials 29:2326–2335CrossRefPubMedGoogle Scholar
  50. 50.
    Collins JM, Uppal R, Incarvito CD, Valentine AM (2005) Inorg Chem 44:3431–3440CrossRefPubMedGoogle Scholar
  51. 51.
    Wang M, Lai TP, Wang L, Zhang H, Yang N, Sadler PJ, Sun H (2015) Chem Commun (Camb) 51:7867–7870CrossRefGoogle Scholar
  52. 52.
    Otwinowski Z, Minor W (1997) Macromol Crystallogr Part A 276:307–326CrossRefGoogle Scholar
  53. 53.
    Winn MD, Ballard CC, Cowtan KD, Dodson EJ, Emsley P, Evans PR, Keegan RM, Krissinel EB, Leslie AG, McCoy A, McNicholas SJ, Murshudov GN, Pannu NS, Potterton EA, Powell HR, Read RJ, Vagin A, Wilson KS (2011) Acta Crystallogr D Biol Crystallogr 67:235–242CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Vagin AA, Steiner RA, Lebedev AA, Potterton L, McNicholas S, Long F, Murshudov GN (2004) Acta Crystallogr D Biol Crystallogr 60:2184–2195CrossRefPubMedGoogle Scholar
  55. 55.
    Mccoy AJ, Grosse-Kunstleve RW, Adams PD, Winn MD, Storoni LC, Read RJ (2007) J Appl Crystallogr 40:658–674CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Yang N, Zhang H, Wang M, Hao Q, Sun H (2012) Sci Rep 2:999CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Punnonen K, Irjala K, Rajamäki A (1997) Blood 89:1052–1057PubMedGoogle Scholar
  58. 58.
    Lundin G, Strom G (1947) Acta Physiol Scand 13:253–266CrossRefPubMedGoogle Scholar
  59. 59.
    Goodwin ML, Harris JE, Hernandez A, Gladden LB (2007) J Diabetes Sci Technol 1:558–569CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Nielsen TT, Sorensen NS (1979) Acta Med Scand 205:303–307CrossRefPubMedGoogle Scholar
  61. 61.
    Fraenkl SA, Muser J, Groell R, Reinhard G, Orgul S, Flammer J, Goldblum D (2011) J Ocul Pharmacol Ther 27:577–580CrossRefPubMedGoogle Scholar
  62. 62.
    Silwood CJ, Grootveld M (2005) Biochem Biophys Res Commun 330:784–790CrossRefPubMedGoogle Scholar
  63. 63.
    Wally J, Halbrooks PJ, Vonrhein C, Rould MA, Everse SJ, Mason AB, Buchanan SK (2006) J Biol Chem 281:24934–24944CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Messori L, Orioli P, Banholzer V, Pais I, Zatta P (1999) FEBS Lett 442:157–161CrossRefPubMedGoogle Scholar
  65. 65.
    Tinoco AD, Saxena M, Sharma S, Noinaj N, Delgado Y, Quinones Gonzalez EP, Conklin SE, Zambrana N, Loza-Rosas SA, Parks TB (2016) J Am Chem Soc 138:5659–5665CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Schlabach MR, Bates GW (1975) J Biol Chem 250:2182–2188PubMedGoogle Scholar
  67. 67.
    Jin Y, Crichton RR (1987) FEBS Lett 215:41–46CrossRefPubMedGoogle Scholar

Copyright information

© SBIC 2018

Authors and Affiliations

  • Justin P. Curtin
    • 1
    Email author
  • Minji Wang
    • 1
  • Tianfan Cheng
    • 1
  • Lijian Jin
    • 1
  • Hongzhe Sun
    • 2
  1. 1.Faculty of DentistryThe University of Hong KongHong KongChina
  2. 2.Department of ChemistryThe University of Hong KongHong KongChina

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