The puzzling issue of silica toxicity: are silanols bridging the gaps between surface states and pathogenicity?

BACKGROUND: Silica continues to represent an intriguing topic of fundamental and applied research across various scientific fields, from geology to physics, chemistry, cell biology, and particle toxicology. The pathogenic activity of silica is variable, depending on the physico-chemical features of the particles. In the last 50 years, crystallinity and capacity to generate free radicals have been recognized as relevant features for silica toxicity. The 'surface' also plays an important role in silica toxicity, but this term has often been used in a very general way, without defining which properties of the surface are actually driving toxicity. How the chemical features (e.g., silanols and siloxanes) and configuration of the silica surface can trigger toxic responses remains incompletely understood. MAIN BODY: Recent developments in surface chemistry, cell biology and toxicology provide new avenues to improve our understanding of the molecular mechanisms of the adverse responses to silica particles. New physico-chemical methods can finely characterize and quantify silanols at the surface of silica particles. Advanced computational modelling and atomic force microscopy offer unique opportunities to explore the intimate interactions between silica surface and membrane models or cells. In recent years, interdisciplinary research, using these tools, has built increasing evidence that surface silanols are critical determinants of the interaction between silica particles and biomolecules, membranes, cell systems, or animal models. It also has become clear that silanol configuration, and eventually biological responses, can be affected by impurities within the crystal structure, or coatings covering the particle surface. The discovery of new molecular targets of crystalline as well as amorphous silica particles in the immune system and in epithelial lung cells represents new possible toxicity pathways. Cellular recognition systems that detect specific features of the surface of silica particles have been identified. CONCLUSIONS: Interdisciplinary research bridging surface chemistry to toxicology is progressively solving the puzzling issue of the variable toxicity of silica. Further interdisciplinary research is ongoing to elucidate the intimate mechanisms of silica pathogenicity, to possibly mitigate or reduce surface reactivity.

Impact of Humidity on Silica Nanoparticle Agglomerate Morphology and Size Distribution.

The effect of humidity on flame-made metal oxide agglomerate morphology and size distribution is investigated, for the first time to our knowledge, and compared to that on soot, which has been widely studied. Understanding the impact of humidity on such characteristics is essential for storage, handling, processing, and eventual performance of nanomaterials. More specifically, broadly used agglomerates of flame-made silica nanoparticles are humidified at various saturation ratios, S = 0.2-1.5, and dried before characterization with a differential mobility analyzer (DMA), an aerosol particle mass (APM) analyzer, and transmission electron microscopy. At high humidity, the constituent single and/or aggregated (chemically bonded) primary particles (PPs) rearrange to balance the capillary forces induced by condensation-evaporation of liquid bridges between PPs. Larger agglomerates restructure more than smaller ones, narrowing their mobility size distribution. After humidification at S = 1.5 and drying, agglomerates collapse into compact structures that follow a fractal scaling law with mass-mobility exponent Dfm = 3.02 ± 0.11 and prefactor km = 0.27 ± 0.07. This critical S = 1.5 for silica agglomerates is larger than the 1.26 obtained for soot because of the hydrophilic surface of silica that delays water evaporation. The relative effective density, ρeff/ρ, of collapsed agglomerates becomes invariant of mobility diameter, dm, similar to that of fluidized and spray-dried granules. The average silica ρeff/ρ = 0.28 ± 0.02 is smaller than the 0.36 ± 0.04 measured for the humidified-dried soot because of the larger size of silica aggregates, dm/ dp, and number of constituent primary particles, np, of diameter dp. This is verified by tandem-DMA (TDMA) measurements, yielding maximum dm = 3 dp or 5 dp and np = 13 or 36 for the soot or silica aggregates studied here, in good agreement with those reported from microscopy and high-pressure agglomerate dispersion. A scaling law relating the initial dm,o to dm, Dfm, and km after condensation-drying is developed. The mass-mobility relationship of collapsed silica and soot agglomerates obtained by combining this law with fast TDMA measurements is in excellent agreement with that measured by the direct, but tedious, DMA-APM analysis.

The silanol content and in vitro cytolytic activity of flame-made silica.

HYPOTHESIS: The surface chemistry of synthetic amorphous silicas is essential for their applicational performance and for understanding their interactions with biological matter. Synthesis of silica by flame spray pyrolysis (FSP) allows to control the content and type of hydroxyl groups which also affects the cytolytic activity. EXPERIMENTS: By controlling the FSP process variables, silica nanoparticles with the same specific surface area but different surface chemistry and content of internal silanols are prepared by combustion of hexamethyldisiloxane sprays, as characterized by Raman and infrared spectroscopy, thermogravimetric analysis, and titration with lithium alanate. Cytolytic activity is assessed in terms of membrane damage in human blood monocytes in vitro. FINDINGS: Unlike commercial fumed silica, FSP-made silicas contain a significant amount of internal silanol groups and a high surface hydroxyl density, up to ∼8OH/nm2, similar to silicas made by wet-chemistry. Increasing the residence time of particles at high temperature during their synthesis reduces the internal and surface hydroxyl content and increases the relative amount of isolated silanols. This suggests incomplete oxidation of the silica matrix especially in short and "cold" flames and indicates that the silica particle formation pathway involves Si(OH)4. The surface chemistry differences translate into lower cytolytic activity for "cold-" than "hot-flame" silicas.

Design and Fabrication of Microspheres with Hierarchical Internal Structure for Tuning Battery Performance.

Microspheres with controlled nano- and macroporosity are fabricated by template-assisted spray drying. Increasing the porosity of the particle up to 20% improves the rate performance of the particles as shown experimentally and by electrochemical simulations of particle lithiation.

On the mechanism of extractive electrospray ionization (EESI) in the dual-spray configuration.

Dual-spray extractive electrospray ionization (EESI) mass spectrometry as a versatile analytical technique has attracted much interest due to its advantages over conventional electrospray ionization (ESI). The crucial difference between EESI and ESI is that in the EESI process, the analytes are introduced in nebulized form via a neutral spray and ionized by collisions with the charged droplets from an ESI source formed by spraying pure solvent. However, the mechanism of the droplet-droplet interactions in the EESI process is still not well understood. For example, it is unclear which type of droplet-droplet interaction is dominant: bounce, coalescence, disruption, or fragmentation? In this work, droplet-droplet interaction was investigated in detail based on a theoretical model. Phase Doppler anemometry (PDA) was employed to investigate the droplet behavior in the EESI plume and provide the experimental data (droplet size and velocity) necessary for theoretical analysis. Furthermore, numerical simulations were performed to clarify the influence of the sheath gas flow on the EESI process. No coalescence between the droplets in the ESI spray and the droplets in the sample spray was observed using various geometries and sample flow rates. Theoretical analysis, together with the PDA results, suggests that droplet fragmentation may be the dominant type of droplet-droplet interaction in the EESI. The interaction time between the ESI droplet and the sample droplet was estimated to be <5 µs. This work gives a clear picture of droplet-droplet interactions in the dual-spray EESI process and detailed information for the optimization of this method for future applications that require higher sensitivity.

The role of nebulizer gas flow in electrosonic spray ionization (ESSI).

In this work, we investigated the role of the nebulizer gas flow in electrosonic spray ionization (ESSI), by systematically studying the relation between the flow and the ion signals of proteins, such as cytochrome c and holomyoglobin using ESSI-mass spectrometry (MS). When a neutral solution was delivered with a small sample flow rate (≤5 µL/min), no obvious transition from electrospray ionization (ESI) to ESSI was found as the gas velocity varies from subsonic to supersonic speed. Droplets mostly experienced acceleration instead of breakup by the high-speed nebulizer gas. On the contrary, using particular experimental conditions, such as an acidic solution or high sample flow rate (≥200 µL/min), more folded protein ions appear to be kept in droplets of diminishing size due to breakup by the high-speed nebulizer gas in ESSI compared with ESI. Theoretical analyses and numerical simulations were also performed to explain the observed phenomena. These systematic studies clarify the ionization mechanism of ESSI and provide valuable insight for optimizing ESSI and other popular pneumatically assisted electrospray ionization methods for future applications.

Uniform nanoparticles by flame-assisted spray pyrolysis (FASP) of low cost precursors.

A new flame-assisted spray pyrolysis (FASP) reactor design is presented, which allows the use of inexpensive precursors and solvents (e.g., ethanol) for synthesis of nanoparticles (10-20 nm) with uniform characteristics. In this reactor design, a gas-assisted atomizer generates the precursor solution spray that is mixed and combusted with externally fed inexpensive fuel gases (acetylene or methane) at a defined height above the atomizing nozzle. The gaseous fuel feed can be varied to control the combustion enthalpy content of the flame and onset of particle formation. This way, the enthalpy density of the flame is decoupled from the precursor solution composition. Low enthalpy content precursor solutions are prone to synthesis of non-uniform particles (e.g., bimodal particle size distribution) by standard flame spray pyrolysis (FSP) processes. For example, metal nitrates in ethanol typically produce nanosized particles by gas-to-particle conversion along with larger particles by droplet-to-particle conversion. The present FASP design facilitates the use of such low enthalpy precursor solutions for synthesis of homogeneous nanopowders by increasing the combustion enthalpy density of the flame with low-cost, gaseous fuels. The effect of flame enthalpy density on product properties in the FASP configuration is explored by the example of Bi(2)O(3) nanoparticles produced from bismuth nitrate in ethanol. Product powders were characterized by nitrogen adsorption, X-ray diffraction, X-ray disk centrifuge, and transmission electron microscopy. Homogeneous Bi(2)O(3) nanopowders were produced both by increasing the gaseous fuel content and, most notably, by cutting the air entrainment prior to ignition of the spray.