Study of the toxicity of inhaled ultrafine engineered powder: example of boehmite nanoparticles

International audienceBoehmite nanoparticles (NP) can be used as a vector for vaccines, replacing conventional adjuvants but also in industry as abrasives, catalysts, substrates for electronic circuits, refractory materials. Thus, the boehmite NP constitutes a good model of study taking into account its various applications: in the industry as well as in the nanomedecine field. This important use of boehmite NP makes particular interest of the evaluation of its potential toxicity. Some toxicological works have been yet performed, the health risk induced by boehmite NP is still not completely characterized. Nevertheless, some authors have shown from In vitro experiments that the boehmite can cause an inflammation characterized by production of IL-8 and a certain cytotoxicity associated with a LDH release. As a result, the boehmite NP must be considered as potential risk factors for health

Study on the toxicity of inhaled alumina nanoparticles: impact of physicochemical properties and adsorption artifacts on the measurement of biological responses

International audienceThis work aims at developping a multidisciplinary approach to highlight the correlation between the toxicity of alumina engineered nanoparticles (NP) and their physicochemical characteristics. Accuracy of measurements depends on cell production after contact with particles, but also depends on the ability of biomolecules to get adsorbed on the NP [1]. That's why, mechanisms of biomolecules adsorption on NP must be fully understood to avoid misinterpretation of data

New insight into artifactual phenomena during <i>in vitro</i> toxicity assessment of engineered nanoparticles: Study of TNF-α adsorption on alumina oxide nanoparticle

International audienceBiomolecules can be adsorbed on nanoparticles (NPs) and degraded during in vitro toxicity assays. These artifactual phenomena could lead to misinterpretation of biological activity, such as false-negative results. To avoid possible underestimation of cytokine release after contact between NP and cells, we propose a methodology to account for these artifactual phenomena and lead to accurate measurements. We focused on the pro-inflammatory cytokine tumor necrosis factor TNF-α. We studied well-characterized boehmite engineered NP [aluminum oxide hydroxide, AlO(OH)]. The rate of TNF-α degradation and its adsorption (on boehmite and on the walls of wells) were determined in cell-free conditions by adding a known TNF-α concentration (1500 pg/ml) under various experimental conditions. After a 24-h incubation, we quantified that 7 wt.% of the initial TNF-α was degraded over time, 6 wt.% adsorbed on the walls of 96-well plates, and 13 wt.% adsorbed on the boehmite surface. Finally, boehmite NP were incubated with murine macrophages (RAW 264.7 cell line). The release of TNF-α was assessed for boehmite NP and the experimental data were corrected considering the artifactual phenomena, which accounted for about 20-30% of the tota

Detection and analysis of nanoparticles in patients: A critical review of the status quo of clinical nanotoxicology

International audienceOn the cusp of massive commercialization of nanotechnology-enhanced products and services, the physical and chemical analysis of nanoparticles in human specimens merits immediate attention from the research community as a prerequisite for a confident clinical interpretationof their occurrence in the human organism. In this review, we describe the caveats in current practices of extracting and isolating nanoparticles from clinical samples and show that they do not help truly define the clinical significance of any detected exogenous nano-sized objects. Finally, we suggest a systematic way of tackling these demanding scientific tasks. More specifically, a precise and true qualitative evaluation of nanoparticles in human biological samples still remains difficult to achieve because of various technical reasons. Such a procedure is more refined when the nature of the pollutants is known, like in the case of nano-sized wear debris originating from biomedical prostheses. Nevertheless, nearly all available analytical methods provide unknown quantitative accuracy and qualitative precision due to the challenging physical and chemical nature of nanoparticles. Without trustworthy information to detect and describe the nanoparticulate load of clinical samples, it is impossible to accurately assess its pathological impact on isolated cases or allow for relevant epidemiological surveys on large populations. Therefore, we suggest that the many and various specimens stored in hospitals be used for the refinement of methods of exhaustive quantitative and qualitative characterization of prominent nanoparticles in complex human milieu

Etude de l'activité biologique de poudres industrielles fines et ultrafines de carbure de silicium : caractérisation physico-chimique.

National audienceL'industrie élabore et utilise des poudres de SiC de plus en plus fines. Depuis leur synthèse jusqu'à leur utilisation finale, les poudres subissent diverses opérations et traitements au cours desquels elles sont susceptibles de se disséminer dans l'atmosphère des locaux industriels, provoquant ainsi un risque d'inhalation. Les particules fines peuvent provoquer une réaction inflammatoire au niveau des poumons. L'objectif de cette étude est d'évaluer la toxicité et d'expliquer la réactivité biologique de différentes variétés de poudres industrielles de SiC

Impact of Airborne Particle Size, Acoustic Airflow and Breathing Pattern on Delivery of Nebulized Antibiotic into the Maxillary Sinuses Using a Realistic Human Nasal Replica

International audiencePurpose:Improvement of clinical outcome in patients with sinuses disorders involves targeting delivery of nebulized drug into the maxillary sinuses. We investigated the impact of nebulization conditions (with and without 100 Hz acoustic airflow), particle size (9.9 μm, 2.8 μm, 550 nm and 230 nm) and breathing pattern (nasal vs. no nasal breathing) on enhancement of aerosol delivery into the sinuses using a realistic nasal replica developed by our team.Methods:After segmentation of the airways by means of high-resolution computed tomography scans, a well-characterized nasal replica was created using a rapid prototyping technology. A total of 168 intrasinus aerosol depositions were performed with changes of aerosol particle size and breathing patterns under different nebulization conditions using gentamicin as a marker.Results:The results demonstrate that the fraction of aerosol deposited in the maxillary sinuses is enhanced by use of submicrometric aerosols, e.g. 8.155 ± 1.476 mg/L of gentamicin in the left maxillary sinus for the 2.8 μm particles vs. 2.056 ± 0.0474 for the 550 nm particles. Utilization of 100-Hz acoustic airflow nebulization also produced a 2- to 3-fold increase in drug deposition in the maxillary sinuses (e.g. 8.155 ± 1.476 vs. 3.990 ± 1.690 for the 2.8 μm particles).Conclusions:Our study clearly shows that optimum deposition was achieved using submicrometric particles and 100-Hz acoustic airflow nebulization with no nasal breathing. It is hoped that our new respiratory nasal replica will greatly facilitate the development of more effective delivery systems in the future

Assessing sinus aerosol deposition: benefits of SPECT-CT imaging

International audiencePurpose: Aerosol inhalation therapy is one of the methods to treat rhinosinusitis. However the topical drug delivery to the posterior nose and paranasal sinuses shows only limited efficiency. A precise sinusal targeting remains a main challenge for aerosol treatment of sinus disorders. This paper proposes a comparative study of the nasal deposition patterns of micron and submicron particles using planar gamma-scintigraphy imaging vs. a new 3-dimensional (3D) imaging approach based on SPECT-CT measurements. Methods: Radiolabelled nebulizations have been performed on a plastinated model of human nasal cast coupled with a respiratory pump. First, the benefits provided by SPECT-CT imaging were compared with 2D gamma-scintigraphy and radioactive quantification of maxillary sinus lavage as reference for the sonic 2.8 μm aerosol sinusal deposition. Then, the impact on nasal deposition of various airborne particle sizes was assessed. Results: The 2D methodology overestimates aerosol deposition in the maxillary sinuses by a factor 9 whereas the 3D methodology is in agreement with the maxillary sinus lavage reference methodology. Then with the SPECT-CT approach we highlighted that the higher particle size was mainly deposited in the central nasal cavity contrary to the submicron aerosol particles (33.8 ± 0.6% of total deposition for the 2.8 μm particles vs. 1 ± 0.3% for the 230 nm particles). Conclusion: Benefits of SPECT/CT for the assessment of radiolabelled aerosol deposition in rhinology are clearly demonstrated. This 3D methodology should be preferentially used for scintigraphic imaging of sinusal deposition in Human

Toxicity assessment of nanoparticles: impact of physico-chemical properties and adsorption artefacts on biological responses

International audienceIn medicine, the uses of nanoparticles (NP) offer new perspectives in imaging (Wagner, 2006), drug delivery (Salmaso, 2004) or radiotherapy (Hainfeld, 2004). However, questions about potential toxic and deleterious effects of nano-structured materials have been raised (Hoet, 2004; Maynard, 2006). Our objective is to develop standardized methods to assess NP toxicity on alveolar macrophages. However, the measurement of biomolecules released in the cell culture supernatants can be modified by their adsorption on the NP. Thus, this adsorption mechanism must be fully understood to avoid misinterpretation of data

Impact of acoustic airflow nebulization on intrasinus drug deposition of a human plastinated nasal cast: New insights into the mechanisms involved

International audienceThe impact of 100 Hz (Hertz) acoustic frequency airflow on sinus drug deposition of aerosols was investigated using a human plastinated nasal cast. The influence of drug concentration and endonasal anatomical features on the sinus deposition enhanced by the 100 Hz acoustic airflow was also examined. Plastinated models were anatomically, geometrically and aerodynamically validated (endoscopy, CT scans, acoustic rhinometry and rhinomanometry). Using the gentamicin as a marker, 286 experiments of aerosol deposition were performed. Changes of airborne particles metrology produced under different nebulization conditions (100 Hz acoustic airflow and gentamicin concentration) were also examined. Aerodynamic and geometric investigations highlighted a global behaviour of plastinated models in perfect accordance with a nasal decongested healthy subject. The results of intrasinus drug deposition clearly demonstrated that the aerosols can penetrate into the maxillary sinuses. The 100 Hz acoustic airflow led to increase the deposition of drug into the maxillary sinuses by a factor 2-3 depending on the nebulization conditions. A differential intrasinus deposition of active substance depending on maxillary ostium anatomical features and drug concentration was emphasized. The existence of a specific transport mechanism of penetration of nebulized particles delivered with acoustic airflow was proposed

Testicular biodistribution of silica-gold nanoparticles after intramuscular injection in mice

International audienceWith the continuing development of nanomaterials, the assessment of their potential impact on human health, and especially human reproductive toxicity, is a major issue. The testicular biodistribution of nanoparticles remains poorly studied. This study investigated whether gold-silica nanoparticlescould be detected in mouse testes after intramuscular injection, with a particular focus on their ability to cross the blood– testis barrier. To that purpose, well-characterized 70-nm gold core–silica shell nanoparticles were used to ensure sensitive detection using high-resolution techniques. Testes were collected at different time points corresponding to spermatogenesis stages in mice. Transmission electronmicroscopy and confocal microscopy were used for nanoparticle detection, and nanoparticle quantification was performed by atomic emission spectroscopy. All these techniques showed that no particles were able to reach the testes. Results accorded with the normal histological appearance of testes even at 45 days post sacrifice.High-resolution techniques did not detect 70-nm silica-gold nanoparticles in mouse testes after intramuscular injection.These results are reassuring about the safety of nanoparticles with regard to male human reproduction, especially in the context of nanomedicine