Significance: Silica particles with a population of nearly free silanols damage cellular membranes and initiate inflammatory reactions. Nearly free silanols are found on the surface of both fractured quartz and amorphous silica particles, and their occurrence initiates the toxicity of silica, thus revisiting the ancient paradigm whereby crystallinity is critical for silica toxicity. This finding resolves the lingering questions about the origin and the variability of the toxicity of silica particles. The discovery of the biological activity of nearly free silanols opens perspectives for the prevention of silicosis through a safer-by-design approach, and will have an impact on other fields that involve interfacial phenomena, including biomaterial design, nanofabrication, and catalysis.

Exposure to some - but not all - quartz particles is associated to silicosis, lung cancer and autoimmune diseases. What imparts pathogenicity to any single quartz source is however still unclear. Crystallinity and various surface features are implied in toxicity. Quartz dusts used so far in particle toxicology have been obtained by grinding rocks containing natural quartz, a process which affects crystallinity and yields dusts with variable surface states. To clarify the role of crystallinity in quartz pathogenicity we have grown intact quartz crystals in respirable size. Quartz crystals were grown and compared with a fractured specimen obtained by grinding the largest synthetic crystals and a mineral quartz (positive control). The key physico-chemical features relevant to particle toxicity - particle size distribution, micromorphology, crystallinity, surface charge, cell-free oxidative potential - were evaluated. Membranolysis was assessed on biological and artificial membranes. Endpoints of cellular stress were evaluated on RAW 264.7 murine macrophages by High Content Analysis after ascertaining cellular uptake by bio-TEM imaging of quartz-exposed cells. Quartz crystals were grown in the submicron (n-Qz-syn) or micron (μ-Qz-syn) range by modulating the synthetic procedure. Independently from size as-grown quartz crystals with regular intact faces did not elicit cellular toxicity and lysosomal stress on RAW 264.7 macrophages, and were non-membranolytic on liposome and red blood cells. When fractured, synthetic quartz (μ-Qz-syn-f) attained particle morphology and size close to the mineral quartz dust (Qz-f, positive control) and similarly induced cellular toxicity and membranolysis. Fracturing imparted a higher heterogeneity of silanol acidic sites and radical species at the quartz surface. Our data support the hypothesis that the biological activity of quartz dust is not due to crystallinity but to crystal fragmentation, when conchoidal fractures are formed. Besides radical generation, fracturing upsets the expected long-range order of non-radical surface moieties - silanols, silanolates, siloxanes - which disrupt membranes and induce cellular toxicity, both outcomes associated to the inflammatory response to quartz.

Nanomaterials often act as a double sword. On the one hand they offer exceptional new properties, but on the other hand show signs of toxicity. High aspect ratio nanomaterials (HARNs) cause more concern than isometric nanoparticles owing to their physical similarity with asbestos. Many compounds may be prepared in fibrous shape with nano-sized diameter differing one from the other in various ways. This article reports a comparative picture of the chemical features and related toxic responses to a variety of HARNs, namely carbon nanotubes, asbestos, carbon nanofibers, oxide and metal wires and rods. In spite of similarities in form, durability and several biological responses elicited in vitro and in vivo, carbon nanotubes - opposite to asbestos - quench radicals, are hydrophobic and may be fully purified from metal impurities. Most of the other HARNs produced so far are metal or metal oxide compounds, less biopersistent than carbon nanotubes.