A multimodal approach combining inductively coupled plasma mass spectrometry (ICP-MS), single-particle ICP-MS (spICP-MS), scanning electron microscopy-energy-dispersive X-ray spectroscopy (SEM-EDS) and Raman spectroscopy enabled a deeper insight into the balance between total titanium (Ti), the soluble titanium fraction and titanium dioxide based particle fraction levels in periprosthetic tissues collected from patients undergoing revision surgery. Hydrofluoric acid usage in the sample digestion allowed for complete digestion of TiO2 particles, thus enabling accurate estimation of total Ti levels. The TiO2 fraction represents 38-94% of the titanium load in the six samples where particles were detected, and the fraction is present mainly in samples from patients with aseptically loosened total hip arthroplasty. Further attention was given to this fraction determining the elemental composition, particle count, particle size and modification of TiO2. The spICP-MS analysis confirmed the presence of the TiO2-derived (nano)particles (NPs) with a 39- to 187-nm median size and particle count up to 2.3 × 1011 particles per gram of tissue. On top of that, the SEM-EDS confirmed the presence of the TiO2 nanoparticles with 230-nm median size and an anatase crystal phase was determined by Raman spectroscopy. This study presents a novel multimodal approach for TiO2 particle determination and characterization in tissue samples and is the first in vivo study of this character.

Department of Analytical Chemistry Faculty of Science Palacký University Olomouc 17 listopadu 12 Olomouc 771 46 Czech Republic

Department of Orthopaedics Faculty of Medicine and Dentistry Palacký University Olomouc University Hospital Olomouc 1 P Pavlova 6 Olomouc 77520 Czech Republic

Transport Research Centre Division of Sustainable Transport and Transport Structures Diagnostics Líšeňská 33a Brno 619 00 Czech Republic

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Advances in ICP-MS-Based Nanoparticle Characterization: Techniques and Challenges in Biological Sample Analysis