title: Reduction of Acute Inflammatory Effects of Fumed Silica Nanoparticles in the Lung by Adjusting Silanol Display through Calcination and Metal Doping.
abstract: The production of pyrogenic (fumed) silica is increasing worldwide at a 7% annual growth rate, including expanded use in food, pharmaceuticals, and other industrial products. Synthetic amorphous silica, including fumed silica, has been generally recognized as safe for use in food products by the Food and Drug Administration. However, emerging evidence from experimental studies now suggests that fumed silica could be hazardous due to its siloxane ring structure, high silanol density, and "string-of-pearl-like" aggregate structure, which could combine to cause membrane disruption, generation of reactive oxygen species, pro-inflammatory effects, and liver fibrosis. Based on this structure-activity analysis (SAA), we investigated whether calcination and rehydration of fumed silica changes its hazard potential in the lung due to an effect on silanol density display. This analysis demonstrated that the accompanying change in surface reactivity could indeed impact cytokine production in macrophages and acute inflammation in the lung, in a manner that is dependent on siloxane ring reconstruction. Confirmation of this SAA in vivo, prompted us to consider safer design of fumed silica properties by titanium and aluminum doping (0-7%), using flame spray pyrolysis. Detailed characterization revealed that increased Ti and Al doping could reduce surface silanol density and expression of three-membered siloxane rings, leading to dose-dependent reduction in hydroxyl radical generation, membrane perturbation, potassium efflux, NLRP3 inflammasome activation, and cytotoxicity in THP-1 cells. The reduction of NLRP3 inflammasome activation was also confirmed in bone-marrow-derived macrophages. Ti doping, and to a lesser extent Al doping, also ameliorated acute pulmonary inflammation, demonstrating the possibility of a safer design approach for fumed silica, should that be required for specific use circumstances.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Sun
authors.affiliation: Foundation Institute of Materials Science (IWT), Department of Production Engineering, University of Bremen , 28359 Bremen, Germany.
authors.forename: Suman
authors.initials: S
authors.lastname: Pokhrel
authors.forename: Darren R
authors.initials: DR
authors.lastname: Dunphy
authors.affiliation: Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , Changchun 130022, Jilin, China.
authors.forename: Haiyuan
authors.initials: H
authors.lastname: Zhang
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Ji
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.forename: Meiying
authors.initials: M
authors.lastname: Wang
authors.forename: Yu-Pei
authors.initials: YP
authors.lastname: Liao
authors.forename: Chong Hyun
authors.initials: CH
authors.lastname: Chang
authors.forename: Juyao
authors.initials: J
authors.lastname: Dong
authors.forename: Ruibin
authors.initials: R
authors.lastname: Li
authors.affiliation: Foundation Institute of Materials Science (IWT), Department of Production Engineering, University of Bremen , 28359 Bremen, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Mädler
authors.affiliation: Self-Assembled Materials Department, Sandia National Laboratories , P.O. Box 5800 MS1349, Albuquerque, New Mexico 87185, United States.
authors.forename: C Jeffrey
authors.initials: CJ
authors.lastname: Brinker
authors.forename: André E
authors.initials: AE
authors.lastname: Nel
authors.forename: Tian
authors.initials: T
authors.lastname: Xia
mesh_terms: D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D053758:Nanoparticles / Q000009:adverse effects* / Q000737:chemistry; D011014:Pneumonia / Q000139:chemically induced* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000633:toxicity; D012821:Silanes / Q000737:chemistry; D012822:Silicon Dioxide / Q000009:adverse effects* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D017382:Reactive Oxygen Species; D012821:Silanes; C082343:silanol; D012822:Silicon Dioxide; D002118:Calcium
keywords: IL-1β; NLRP3 inflammasome; doping; fumed silica; lung inflammation; silanol groups