Potential neurotoxicity of titanium implants: Prospective, in-vivo and in-vitro study

Shahar Shelly, Sigal Liraz Zaltsman, Ofir Ben-Gal, Avraham Dayan, Ithamar Ganmore, Chen Shemesh, Dana Atrakchi, Sharif Garra, Orly Ravid, Daniel Rand, Hila Israelov, Tayir Alon, Gabriel Lichtenstein, Shirley Sharabi, David Last, Fabien Gosselet, Vasiliy Rosen, Gideon Burstein, Alon Friedlander, Ran HarelGuy Vogel, Michal Schnaider Beeri, Yael Mardor, Yair Lampl, Gideon Fleminger, Itzik Cooper*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Titanium dioxide (TiO2) is a frequently used biomaterial, particularly in orthopedic and dental implants, and it is considered an inert and benign compound. This has resulted in toxicological scrutiny for TiO2 in the past decade, with numerus studies showing potential pathologic downstream effects. Herein we describe case report of a 77-year-old male with subacute CNS dysfunction, secondary to breakdown of a titanium-based carotid stent and leading to blood levels 1000 times higher (3 ppm) than the reported normal. We prospectively collected tissues adjacent to orthopedic implants and found a positive correlation between titanium concentration and time of implant in the body (r = 0.67, p < 0.02). Rats bearing titanium implants or intravascularly treated with TiO2 nanoparticles (TiNP) exhibited memory impairments. A human blood-brain barrier (BBB) in-vitro model exposed to TiNP showed paracellular leakiness, which was corroborated in-vivo with the decrease of key BBB transcripts in isolated blood vessels from hippocampi harvested from TiNP-treated mice. Titanium particles rapidly internalized into brain-like endothelial cells via caveolae-mediated endocytosis and macropinocytosis and induced pro-inflammatory reaction with increased expression of pro-inflammatory genes and proteins. Immune reaction was mediated partially by IL-1R and IL-6. In summary, we show that high levels of titanium accumulate in humans adjacent to orthopedic implants, and our in-vivo and in-vitro studies suggest it may be neurotoxic.

Original languageEnglish
Article number121039
JournalBiomaterials
Volume276
DOIs
StatePublished - Sep 2021

Funding

FundersFunder number
Aaron Gutwirth Fund
Defense Threat Reduction Agency-Joint Science & Technology Office for Chemical & Biological Defense11816372
Nehemia Rubin Excellence in Biomedical Research
Ministry of Science and Technology, Israel3-13576

    Keywords

    • Blood-brain barrier
    • Learning and memory
    • Neurotoxicity
    • Orthopedic implants
    • Titanium nanoparticles

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