Osseointegration mechanisms: a proteomic approach

  • N. Araújo-Gomes
  • F. Romero-Gavilán
  • I. García-Arnáez
  • C. Martínez-Ramos
  • A. M. Sánchez-Pérez
  • M. Azkargorta
  • F. Elortza
  • J. J. Martín de Llano
  • M. Gurruchaga
  • I. Goñi
  • J. Suay
Original Paper


The prime objectives in the development of biomaterials for dental applications are to improve the quality of osseointegration and to short the time needed to achieve it. Design of implants nowadays involves changes in the surface characteristics to obtain a good cellular response. Incorporating osteoinductive elements is one way to achieve the best regeneration possible post-implantation. This study examined the osteointegrative potential of two distinct biomaterials: sandblasted acid-etched titanium and a silica sol–gel hybrid coating, 70% MTMOS-30% TEOS. In vitro, in vivo, and proteomic characterisations of the two materials were conducted. Enhanced expression levels of ALP and IL-6 in the MC3T3-E1 cells cultured with coated discs, suggest that growing cells on such surfaces may increase mineralisation levels. 70M30T-coated implants showed improved bone growth in vivo compared to uncoated titanium. Complete osseointegration was achieved on both. However, coated implants displayed osteoinductive properties, while uncoated implants demonstrated osteoconductive characteristics. Coagulation-related proteins attached predominantly to SAE-Ti surface. Surface properties of the material might drive the regenerative process of the affected tissue. Analysis of the proteins on the coated dental implant showed that few proteins specifically attached to its surface, possibly indicating that its osteoinductive properties depend on the silicon delivery from the implant.

Graphical abstract


Osteogenesis Bone regeneration Coagulation Osteoinduction Biointerfaces 



This work was supported by MAT2017-86043-R (MINECO); Universidad Jaume I under UJI-B2017-37 and Grant Predoc/2014/25; University of the Basque Country (UPV/EHU) through UFI11/56; Basque Government through IT611-13 and Grant Predoc/2016/1/0141, and Generalitat Valenciana under Grant Grisolia/2014/016. Authors would like to thank Antonio Coso and Jaime Franco (GMI-Ilerimplant) for their inestimable contribution to this study, and Raquel Oliver, José Ortega (UJI) and Iraide Escobes (CIC bioGUNE) for their valuable technical assistance.


  1. 1.
    Khan WS, Rayan F, Dhinsa BS, Marsh D (2012) An osteoconductive, osteoinductive, and osteogenic tissue-engineered product for trauma and orthopaedic surgery: how far are we? Stem Cells Int. Article ID 236231, 7.
  2. 2.
    Charyeva O, Altynbekov K, Zhartybaev R, Sabdanaliev A (2012) Long-term dental implant success and survival–a clinical study after an observation period up to 6 years. Swed Dent J 36:1–6PubMedGoogle Scholar
  3. 3.
    Le Guéhennec L, Soueidan A, Layrolle P, Amouriq Y (2007) Surface treatments of titanium dental implants for rapid osseointegration. Dent Mater 23:844–854. CrossRefPubMedGoogle Scholar
  4. 4.
    Solheim E (1998) Osteoinduction by demineralised bone. Int Orthop 22:335–342. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Wilson-Hench J (1987) Osteoinduction. In: Williams DF (ed) Progress in biomedical engineering, Defin Biomater, vol 4. Elsevier, p 29Google Scholar
  6. 6.
    Carlsson L, Röstlund T, Albrektsson B et al (1986) Osseointegration of titanium implants. Acta Orthop Scand 57:285–289. CrossRefPubMedGoogle Scholar
  7. 7.
    Eckert SE, Koka S (2006) Osseointegrated dental implants. In: Johnson FE, Virgo KS, Lairmore TC, Audisio RA (eds) The bionic human, Humana Press.
  8. 8.
    Buser D, Broggini N, Wieland M et al (2004) Enhanced bone apposition to a chemically modified SLA titanium surface. J Dent Res 83:529–533. CrossRefPubMedGoogle Scholar
  9. 9.
    Martinez-Ibañez M, Juan-Diaz MJ, Lara-Saez I et al (2016) Biological characterization of a new silicon based coating developed for dental implants. J Mater Sci Mater Med 27:80. CrossRefPubMedGoogle Scholar
  10. 10.
    Romero-Gavilán F, Barros-Silva S, García-Cañadas J et al (2016) Control of the degradation of silica sol-gel hybrid coatings for metal implants prepared by the triple combination of alkoxysilanes. J Non Cryst Solids 453:66–73. CrossRefGoogle Scholar
  11. 11.
    Reffitt DM, Ogston N, Jugdaohsingh R et al (2003) Orthosilicic acid stimulates collagen type 1 synthesis and osteoblastic differentiation in human osteoblast-like cells in vitro. Bone 32:127–135. CrossRefPubMedGoogle Scholar
  12. 12.
    Ha SW, Neale Weitzmann M, Beck GR (2014) Bioactive silica nanoparticles promote osteoblast differentiation through stimulation of autophagy and direct association with LC3 and p62. ACS Nano 8:5898–5910. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Schmidt DR, Waldeck H, Kao WJ (2009) Protein adsorption to biomaterials. In: Puleo DA, Bizios R (eds) Biological interactions on materials surfaces: understanding and controlling protein, cell, and tissue, Springer.
  14. 14.
    Chen Z, Klein T, Murray RZ et al (2015) Osteoimmunomodulation for the development of advanced bone biomaterials. Mater Today 19:304–321. CrossRefGoogle Scholar
  15. 15.
    Calciolari E, Donos N (2018) The use of omics profiling to improve outcomes of bone regeneration and osseointegration. How far are we from personalized medicine in dentistry? J Proteomics. PubMedGoogle Scholar
  16. 16.
    Romero-Gavilán F, Gomes NC, Ródenas J et al (2017) Proteome analysis of human serum proteins adsorbed onto different titanium surfaces used in dental implants. Biofouling 33:98–111. CrossRefPubMedGoogle Scholar
  17. 17.
    Ajai S, Sabir A (2013) Evaluation of serum alkaline phosphatase as a biomarker of healing process progression of simple diaphyseal fractures in adult patients. Int Res J Biol Sci Int Res J Biol Sci 2:2278–3202Google Scholar
  18. 18.
    Li Y, Bäckesjö C-M, Haldosén L-A, Lindgren U (2008) IL-6 receptor expression and IL-6 effects change during osteoblast differentiation. Cytokine 43:165–173. CrossRefPubMedGoogle Scholar
  19. 19.
    Huang W, Yang S, Shao J, Li Y-P (2007) Signaling and transcriptional regulation in osteoblast commitment and differentiation. Front Biosci 12:3068–3092. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Al-maawi S, Orlowska A, Sader R et al (2017) In vivo cellular reactions to different biomaterials—physiological and pathological aspects and their consequences. Semin Immunol 29:49–61. CrossRefPubMedGoogle Scholar
  21. 21.
    Hirsh SL, McKenzie DR, Nosworthy NJ et al (2013) The Vroman effect: competitive protein exchange with dynamic multilayer protein aggregates. Colloids Surf B Biointerfaces 103:395–404. CrossRefPubMedGoogle Scholar
  22. 22.
    Falgarone G, Chiocchia G (2009) Clusterin: a multifacet protein at the crossroad of inflammation and autoimmunity. Adv Cancer Res 104:139–170. CrossRefPubMedGoogle Scholar
  23. 23.
    Cho NH, Seong SY (2009) Apolipoproteins inhibit the innate immunity activated by necrotic cells or bacterial endotoxin. Immunology 128:479–486. CrossRefGoogle Scholar
  24. 24.
    Loi F, Córdova LA, Pajarinen J et al (2016) Inflammation, fracture and bone repair. Bone 86:119–130. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Chu AJ (2010) Blood coagulation as an intrinsic pathway for proinflammation: a mini review. Inflamm Allergy Drug Targets 9:32–44. CrossRefPubMedGoogle Scholar
  26. 26.
    Wehner C, Janjić K, Agis H (2017) Relevance of the plasminogen system in physiology, pathology, and regeneration of oral tissues—from the perspective of dental specialties. Arch Oral Biol 74:136–145. CrossRefPubMedGoogle Scholar
  27. 27.
    Wakabayashi S, Koide T (2011) Histidine-rich glycoprotein: a possible modulator of coagulation and fibrinolysis. Semin Thromb Hemost 37:389–394. CrossRefPubMedGoogle Scholar
  28. 28.
    Kolte D, Shariat-Madar Z (2016) Plasma Kallikrein inhibitors in cardiovascular disease an innovative therapeutic approach. Cardiol Rev 24:99–109. CrossRefPubMedGoogle Scholar
  29. 29.
    Schmaier AH, McCrae KR (2007) The plasma kallikrein-kinin system: its evolution from contact activation. J Thromb Haemost 5:2323–2329. CrossRefPubMedGoogle Scholar
  30. 30.
    Niemeier A, Schinke T, Heeren J, Amling M (2012) The role of apolipoprotein E in bone metabolism. Bone 50:518–524. CrossRefPubMedGoogle Scholar
  31. 31.
    Rivera-Chacon DM, Alvarado-Velez M, Acevedo-Morantes CY et al (2013) Fibronectin and vitronectin promote human fetal osteoblast cell attachment and proliferation on nanoporous titanium surfaces. J Biomed Nanotechnol 9:1092–1097. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Ru D-W, Yan Y-F, Li B et al (2016) Tetranectin knock-out mice exhibit features of kyphosis and osteoporosis. Fudan Univ J Med Sci 43:159. Google Scholar
  33. 33.
    Albrektsson T, Johansson C (2001) Osteoinduction, osteoconduction and osseointegration. Eur Spine J 10:96–101. CrossRefGoogle Scholar
  34. 34.
    Martínez-Ibáñez M, Murthy NS, Mao Y et al (2017) Enhancement of plasma protein adsorption and osteogenesis of hMSCs by functionalized siloxane coatings for titanium implants. J Biomed Mater Res Part B Appl Biomater 106:1138–1147. CrossRefPubMedGoogle Scholar

Copyright information

© SBIC 2018

Authors and Affiliations

  • N. Araújo-Gomes
    • 1
    • 2
  • F. Romero-Gavilán
    • 1
  • I. García-Arnáez
    • 3
  • C. Martínez-Ramos
    • 2
  • A. M. Sánchez-Pérez
    • 2
  • M. Azkargorta
    • 4
  • F. Elortza
    • 4
  • J. J. Martín de Llano
    • 5
  • M. Gurruchaga
    • 3
  • I. Goñi
    • 3
  • J. Suay
    • 1
  1. 1.Departamento de Ingeniería de Sistemas Industriales y DiseñoUniversitat Jaume ICastellónSpain
  2. 2.Department of MedicineUniversitat Jaume ICastellónSpain
  3. 3.Facultad de Ciencias QuímicasUniversidad del País VascoSan SebastiánSpain
  4. 4.Proteomics Platform, CIC bioGUNE, CIBERehd, ProteoRed-ISCIII, Bizkaia Science and Technology ParkDerioSpain
  5. 5.Department of Pathology, Faculty of Medicine and DentistryHealth Research Institute of the Hospital Clínico (INCLIVA), University of ValenciaValenciaSpain

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