1 Custom-Designed Nanomaterial Libraries 2 for Testing Metal Oxide Toxicity 3 SUMAN POKHREL, † ANDR  E E. NEL, ‡ AND LUTZ M € ADLER* , † 4 † Foundation Institute of Materials Science (IWT), Department of Production 5 Engineering, University of Bremen, Germany, and ‡ Department of 6 Medicine-Division and California NanoSystems Institute, University of California, 7 Los Angeles, California, United States 8 RECEIVED ON JANUARY 29, 2012 CONSPECTUS 9 10 A dvances in aerosol technology over the past 10 years have enabled 11 the generation and design of ultrafine nanoscale materials for many 12 applications. A key new method is flame spray pyrolysis (FSP), which 13 produces particles by pyrolyzing a precursor solution in the gas phase. FSP 14 is a highly versatile technique for fast, single-step, scalable synthesis of 15 nanoscale materials. New innovations in particle synthesis using FSP 16 technology, including variations in precursor chemistry, have enabled 17 flexible, dry synthesis of loosely agglomerated, highly crystalline ultrafine 18 powders (porosity g 90%) of binary, ternary, and mixed-binary-and- 19 ternary oxides. FSP can fulfill much of the increasing demand, especially in 20 biological applications, for particles with specific material composition, 21 high purity, and high crystallinity. 22 In this Account, we describe a strategy for creating nanoparticle libraries (pure or Fedoped ZnO or TiO 2 ) utilizing FSP and using these 23 libraries to test hypotheses related to the particles' toxicity. Our innovation lies in the overall integration of the knowledge we have 24 developed in the last 5 years in (1) synthesizing nanomaterials to address specific hypotheses, (2) demonstrating the electronic properties 25 that cause the material toxicity, (3) understanding the reaction mechanisms causing the toxicity, and (4) extracting from in vitro testing and 26 in vivo testing in terrestrial and marine organisms the essential properties of safe nanomaterials. 27 On the basis of this acquired knowledge, we further describe how the dissolved metal ion from these materials (Zn 2þ in this 28 Account) can effectively bind with different cell constituents, causing toxicity. We use FeÀS protein clusters as an example of the 29 complex chemical reactions taking place after free metal ions migrate into the cells. 30 As a second example, TiO 2 is an active material in the UV range that exhibits photocatalytic behavior. The induction of 31 electronÀhole (e À /h þ ) pairs followed by free radical production is a key mechanism for biological injury. We show that decreasing 32 the bandgap energy increases the phototoxicity in the presence of near-visible light. We present in detail the mechanism of electron 33 transfer in biotic and abiotic systems during light exposure. Through this example we show that FSP is a versatile technique for 34 efficiently designing a homologous library, meaning a library based on a parent oxide doped with different amounts of dopant, and 35 investigating the properties of the resulting compounds. 36 Finally, we describe the future outlook and state-of-the-art of an innovative two-flame system. A double-flame reactor enables 37 independent control over each flame, the nozzle distances and the flame angles for efficient mixing of the particle streams. In 38 addition, it allows for different flame compositions, flame sizes, and multicomponent mixing (a grainÀgrain heterojunction) during 39 the reaction process. 40 Introduction 41 Many industrial sectors such as catalyst manufacturing, com- 42 posite materials or passive electronic components include 43 nanoparticles (NPs) in their processes. The market for nano- 44 technology based electronic components and pharmaceuticals 45 was $147 billion in 2007 and is expected to reach $2.5 trillion 46 by 2015. 1,2 Over the past decade, newly developed NPs have 47 been found to exhibit fascinating properties. 3 The develop- 48 ment in NP production, especially their specific design, was 49 mostly realized during the last 20 years. Initially, wet chemical Accounts of Chemical Research | 3b2 | ver.9 | 21/11/012 | 21:58 | Msc: ar-2012-00032q | TEID: drh00 | BATID: 00000 | Pages: 9.85 www.pubs.acs.org/accounts Vol. XXX, No. XX ’ XXXX ’ 000–000 ’ ACCOUNTS OF CHEMICAL RESEARCH ’ A 10.1021/ar300032q & XXXX American Chemical Society