Nanoparticles - what's now, what's next?

The term "nanoparticle" refers to a crystallite or primary particle measuring less than 100 nm in size. This article will focus primarily on inorganic nanoparticles that are produced in the form of dry powders or liquid dispersions and, in many cases, further processed into higher value-added products, such as slurries, films or devices, for use in commercial applications. It will focus on select nanoparticle applications that can be classified as "hot," "warm," or "emerging." The ambiguities inherent to the definition of nanotechnology, combined with the extraordinary breadth of the field have led to inconsistencies in market estimates and forecasts. According to the National Science Foundation (NSF; nsf.gov), the global market for nanotechnology-related products and services will reach $1 trillion by 2015 (1). Based on the NSF's projections, the Nanobusiness Alliance (nanobusiness.org) forecasts that the nanotechnology market will reach $225 billion by 2005. In rather stark contrast, CMP Cientifica (cientifica.com), a market research firm based in Europe (2), reports nanotechnology revenues at $30 million/yr - four orders of magnitude smaller than Nanobusiness Alliance's estimate. The best approach to take in calculating the market potential for nanotechnology products is to carefully define what is being measured, since the "raw" nanomaterial will have a substantially different market price than the value-added end product, such as a coating or device. The total world market for nanoparticulate materials reached an estimated $555.6 million in 2001 and is expected to rise at a 12.8%/ yr, exceeding $900 million in 2005 (2). Electronic, magnetic and optoelectronic applications for nanoparticles will account for 74.2% of the 2005 market; biomedical, pharmaceutical and cosmetic applications will account for 16.1%; and energy, catalytic and structural applications will account for the remaining 9.8%, according to a Business Communications Co. (BCC; bccresearch.com) report series (4). Academic and industrial research has shown that control over a nanoparticle's size, shape, consistency and composition are necessary to ensure that the nanoparticle will be made to comply with future requirements and be tailored for specific commercial applications. Consequently, existing manufacturing techniques are being continuously refined while at the same time novel production methods are being developed (see sidebar, p. 40S). Today, the most commercially important nanoparticulate materials are simple metal oxides, such as silica (SiO^sub 2^), titania (TiO^sub 2^), alumina (Al^sub 2^O^sub 3^), iron oxide (Fe^sub 3^O^sub 4^, Fe^sub 2^O^sub 3^), zinc oxide (ZnO), ceria (CeO^sub 2^) and zirconia (ZrO^sub 2^). Also of increasing importance are mixed oxides, such indium-tin oxide (In^sub 2^O^sub 3^-SnO^sub 2^ or ITO) and antimony-tin oxide (ATO), silicates (aluminum and zirconium silicates) and titanates (barium titanate (BaTiO^sub 3^)). While silica and iron oxide nanoparticles have a commercial history spanning half a century or more, nanocrystalline TiO^sub 2^, ZnO, CeO^sub 2^, ITO and other oxides have more recently entered the marketplace. Other types of nanoparticles, including various complex oxides, semiconductors, nonoxide ceramics (e.g., tungsten carbide) and metals are also under development and available from some companies in laboratory- and pilot-scale quantities. With the exception of semiconducting oxides, such as TiO^sub 2^ and ITO, semiconductor nanocrystals (often called quantum dots) are not yet used in large- scale commercial applications. One technological problem limiting the usage of metal nanoparticles in some applications is their high reactivity, which makes it difficult to produce, transfer and store metal nanopowders without particle contamination. In some cases, the high surface area of the particles increases their pyrophoricity, which poses safety hazards. Chemical-mechanical polishing - here today and hot An important opportunity for nanoparticles in the area of computers and electronics is their use in a special polishing process, chemical- mechanical polishing or chemical-mechanical planarization (CMP), that is critical to semiconductor chip fabrication. CMP is used to obtain smooth, flat, and defect-free metal and dielectric layers on silicon wafers. This process utilizes a slurry of oxide nanoparticles and relies on mechanical abrasion as well as a chemical reaction between the slurry and the film being polished. CMP is also used in some other applications, such as the polishing of magnetic hard disks. The leading global producers of slurries for CMP applications are Cabot Microelectronics (cabot-corp.com) and Rodel (rodel.com), although other suppliers of abrasive particles and/or slurries have emerged, including Alcoa World Chemicals (alumina.alcoa.com), Honeywell (honeywell.com), Baikowski Chimie (baikowski.com), Bayer Corp. (bayer.com), Clariant Corp. (clariant.com), DuPont AirProducts Nanomaterials (nanoslurry.com), Eka Chemicals (ekachemicals.se), EKC Technology, Inc. (ekctech.com), Ferro Corp. (ferro.com), Fujimi Corp. (fujimico.com), JSR Micro (jsrusa.com), Malakoff Industries (subsidiary of Reynolds Metals Co.; rmc.com), 3M Co. (mmm.com), Nanophase Technologies (nanophase.com), Nissan Chemical Industries (nissanchem.co.jp), Nanoproducts Corp. (nanoproducts.com), Olin Microelectronics Materials (a subsidiary of Arch Chemicals; archchemicals.com), Praxair Surface Technologies (praxair.com) and Wacker Silicones (wacker.com). The market for CMP slurries is valued at around $400 million, with a growth rate of over 20%/yr. Nanoparticles - typically silica or alumina, although other oxides, such as CeO^sub 2^, are increasing in importance - are a basic requirement of every slurry produced. Studies have demonstrated conclusively that the probability of microscratching can be reduced significantly by using slurries with particle size distributions in the 100-nm range or smaller. Growth in the consumption of abrasive nanoparticles for CMP will be driven primarily by an increase in the number of semiconductor wafers processed, a rise in the percentage of wafers that are processed using CMP, and an increase in the number of layers per wafer that are planarized. Currently, CMP is the only known technique that can satisfy the die-level flatness requirements of sub-0.18-[mu]m devices. The emergence of copper in wafer- fabrication processes and the semiconductor industry's roadmap towards smaller design rules are expected to fuel the development of more-precisely engineered nanoparticles and compositions beyond silicon oxide, aluminum oxide and cerium oxide. Drug delivery - futuristic, but hot Particulate drug carriers can act as delivery vehicles for drugs administered orally or injected into the bloodstream. Such carriers play a key role in the development of site-specific drug-delivery technologies that allow drugs, vaccines and DNA to be transferred to targeted cells and tissues without negatively impacting other areas of the body (see sidebar, p. 41S). The primary competition in this market segment stems from the arduous approval process of the Food and Drug Administration (fda.gov) and similar international regulatory bodies. Drug-delivery technologies based on inorganic carrier particles and polymeric nanocomposite particles are subject to the same rigorous development, testing and evaluation processes required of new drug compounds. Thus far, tests conducted on nanoparticle drug-delivery technologies have yielded promising results, but commercialization of these innovations is years away. One reason is that some approaches to using nanoparticles for drug delivery suffer from less- than-ideal functionalization (3). Nanocapsules, on the other hand, (e.g., spheres or micelles formed by surfactants, which contain nanoscopic droplets of drug) often lack the stability needed to reach their target in the body before disintegrating. However, companies such as Capsulution NanoScience AG (capsulution.com) are working on building up the walls of nanoscale drug-delivery capsules in a layer-by-layer (LBL) fashion via its proprietary LBL- Technology (Figure). A competitive and complementary technology (with regard to nanoparticles and nanocapsules) involves the use of dendrimers (highly branched synthetic polymer) to deliver drugs. Drugs are attached to the dendrimer's surface or placed in the voids inside them for site targeting and controlled delivery, or a combination of targeting and detection. Drug-delivery capsules. Courtesy of Capsulution NanoScience. Sunscreens - here today and warm/hot Overexposure to ultraviolet (UV) radiation is harmful to humans and can lead to sunburn, photoaging of the skin, and various skin cancers. A range of active ingredients are used in sunscreen products to provide UV radiation protection. They can be classified according to the portion of the UV spectrum they screen out, or by their chemical nature - that is, whether they are organic or inorganic. Although TiO^sub 2^ and Zn^sub 2^O^sub 3^ have been known to physically block both long- and short-wavelength ultraviolet radiation (UVA and UVB rays, respectively), these inorganic active ingredients have penetrated the sunscreen market much more slowly than their organic competitors.The primary reason is that these inorganic sunscreens appear white on the skin - an aesthetic drawback. However, the nanosize particles dispersed in newer formulations transmit visible light and therefore act as transparent sunblocks. Among the companies producing TiO^sub 2^ and ZnO nanocrystals and/ or dispersions are: BASF (basf.com), Degussa, Elementis Specialties (elementis-specialties.com), Ishihara Techno Corp. (ISK; iijnet.or.jp/itc-fmp/), Kemira Pigments (kemira.com), Millennium Chemicals (millenniumchem.com), Nanophase Technologies, NanoProducts Corp., Showa Denko (sdk.co.jp), Uniqema Solaveil (uniqema.com), SunSmart (sunsmart.com.au, Tayca (tayca.co.jp), and Zinc Corp. of America (zinccorp.com). One marketing advantage of inorganic particles is the ability to provide broad-spectrum protection in a non-irritating sunscreen product. Certain organic active agents, including avobenzone (also known as Parsol-1789), which provides full UVA shielding, can cause skin irritation. As a result, TiO^sub 2^ and ZnO are finding increasing application in sensitive skin and baby products (e.g., Clinique; clinique.com and Johnson & Johnson; jnj.com) specialty-sunscreen brands (e.g., Cellex-C International's (cellex-c.com) Cellex-C and Obagi's (obagi.com) skin-care line), and daily-wear skin lotions and foundations that provide UV protection (e.g., Oil of Olay, Revlon). One concern regarding the use of metal oxide nanoparticles, is that upon absorption of UV radiation, they release free radicals, which can damage DNA, and thus cause cancer. Oxonica (oxonica.com) is working on coating the nanoparticles with a substance that would allow the free radicals to recombine before entering the skin (3). Existing suppliers of nanoparticles also generally offer the particles with coatings. However, a recent factor that may complicate the use of organic and inorganic nanoparticles alike is concern about the fate of the particles when applied to the skin, as they can penetrate much deeper than microparticles. At any rate, with a few exceptions, organic sunscreen active agents are more widely used than TiO^sub 2^ or ZnO by the world's leading sun-care product manufacturers. For example, LOreal's (loreal.com) Ombrelle, Schering-Plough's (schering.de) Coppertone, and Playtex's (playtex.com) Banana Boat products almost exclusively employ organic agents, such as octyl methoxycinnamate, oxybenzone and avobenzone as sunscreen active ingredients. As the industry develops and matures, nanomaterials will increasingly become more affordable and cost competitive with conventional materials while offering superior or novel performance. The volume and pricing of nanomaterials is already in the range where a number of commercial applications are economically compelling. With the availability of such nanomaterials as building blocks and associated processing know-how, a commercial world based on nanotechnology is beginning to emerge. Fighting Disease at the Nanoscale CARRIER PARTICLES FOR DRUG DELIVERY are typically synthesized from organic materials, such as lipids, polymers and liposomes. However, several inorganic nano-sized carriers are under development, including magnetic particles, semiconductor quantum dots, calcium phosphate and colloidal gold. A handful of firms and institutions are developing nanoscale inorganic particles for drug- delivery applications. The importance of targeted drug delivery technology is illustrated by the shortcomings of chemotherapy, which is commonly used to treat many types of cancers. Because of the difficulty of localizing cancer drugs at the tumor site in chemotherapy treatments, the patient suffers toxic side effects. Innovative work by researchers from the State Univ. of New York at Buffalo (buffalo.edu), in conjunction with Nanobiotix (nanobiotix.com) demonstrates how superparamagnctic iron-oxide nanocrystals encased within a silica shell (a.k.a., magnetic "nanoclinics") can be engineered to selectively hunt down breast and ovarian cancer cells and destroy them upon application of a magnetic field during a magnetic resonance imaging (MRI) procedure. Similarly, General Electric (ge.com) is exploring the use of nanoparticles in MRI and similar medical applications. Another promising anti-cancer treatment using nanoparticles involves the use of antibodies. Cytlmmune Sciences (cytimmune.com) has successfully bound an anti-cancer protein biologic dubbed "TNF" to gold nanocrystals and delivered them safely and effectively to tumor-ridden mice and dogs. Meanwhile, scientists from the Univ. of California at San Diego (ucsd.edu) have designed semiconductor nanocrystals (quantum dots) coated with "homing peptides" that target specific types of cancer cells in live mice. Their next step is to synthesize quantum dots that are functionalized with both homing peptides and cancer treatment drugs, which will target and destroy the cancerous tissue. Nanoparticles are also being used to deliver drugs and vaccines into cells. To this end, pSIMedica (psivida.com.au.com) is applying nanostructured porous silicon known as BioSilicon, while BioSante Pharmaceuticals (biosantepharma.com) is using calcium phosphate nanoparticles (called CAPS) for drug delivery through the eye, a technology that has successfully completed pre-clinical trials. BioSante's nanoparticles are also used in other therapies, including an oral insulin-delivery system, a tuberculosis-vaccine delivery system, and as mucosal vaccine adjuvants (i.e., particles that deliver soluble antigens through nasal mucus; to induce immune responses). The formulation of drug compounds into nanoparticulate form in order to increase the solubility and efficacy of various drugs is also in development. American Pharmaceutical Partners (appdrugs.com) has created a nanoparticulate form of paclitaxel, the active ingredient in Taxol, a widely used cancer-fighting agent, and recently launched clinical phase III trials. Similarly, CritiTech (crititech.com), through a process known as precipitation with compressed antisolvent (PCA), has created a nanoparticulate form of paclitaxel that is currently in clinical phase I trials. Advectus Life Sciences (advectuslifesciences.com) has launched clinical phase II trials with a nanoparticle-based technology called Nanocure, which transfers cancer-fighting drugs across the blood-brain barrier. Using a different approach, Novartis Pharma (novartis.com) is investigating the use of dendrimers as nanoparticles to prevent an immune response during the transplant of organs of animal origin. - Rita D'Aquino Nanoparticles in the Making HISTORICAL PROCESSES HAVE PAVED THE way to manufacturing nanomaterials. Now, innovative routes are being explored and developed. While an exhaustive review of all these methods is beyond the scope of this article, some of the novel nanomaterial manufacturing methods under development include: 1. Attrition methods - these methods attempt to break coarse micron-sized particles into smaller particles through application of directed energy, such as milling. Some teams are exploring ways to perform the milling in a carefully controlled thermal, shear and chemical environments. While appropriate for certain applications, these techniques have been reported to yield a product that is contaminated with the media or vessel used to break the particles. Cost, yield and scalability are other issues that must be addressed. Nanoparticle compositions produced using cost-effective attrition methods can be marketed in the $50-500/kg range in tons-per-year volumes. Companies that use or have used attrition or mechanochemical methods are: * Advanced Powder Technology (apt-powders.com) * Altair Nanotechnologies (altairnano.com) * NanoSystems (nanocrystal.com) * Samsung Corning (samsung.com) * Buhler AG (buhlergroup.com/nano/en). 2. Vapor methods - these methods are used to make metallic and metal oxide ceramic nanoparticles and non-agglomerated particles that are necessary for transparent scratch-resistant coatings and for modifying properties of plastics. They involve first directly vaporizing selected raw materials or combusting the raw materials with a reactant gas, such as oxygen (when making oxides) or an inert gas (when making metal nanoparticles) at temperatures ranging from 1,500 to 2,300 K. Next, the vapor is quenched to form powder nanoparticles. Attractive features of these processes are the low contamination levels of the product and diverse range of compositions that can be produced. Final particle size is controlled by variation of parameters such as temperature, gas environment and evaporation rate. Drawbacks include high-energy costs due to the high temperature requirements and, if the quench is accomplished by the addition of coolants, high raw material and separation costs. Certain methods of feeding precursors and achieving higher temperatures (e.g., electrical energy) may limit the flexibility and scalability of the process. Nanoparticle compositions produced using cost-effective vapor methods can be marketed in the $20-$200/kg range in tons-per- year volumes. Larger volumes are expected to permit pricing in the $5-$50/kg range. Companies that have used vapor phase methods include: * Cabot (cabot.com) * Degussa (advanced-nano.com) * NanoProducts (nanoproducts.com) * Nanophase Technologies (nanophase.com) * Tal Materials (talmaterials.com) * NanoTechnologies (nanoscale.com) * Hosokawa Micron (hosokawa.com) * QinetiQ Nanomaterials Ltd. (qinetiq.com) * Toshiba (toshiba.com). In fact, Toshiba has developed a new nanoparticle production method based on the chemical vapor deposition (CVD) technique. Both liquid and gas forms of a substance are fed to a reactor. Particles of various shapes and sizes are created depending on the gas-to- liquid ratio, the order of addition of gas and liquid, and the temperature and length of time during which heat is applied. The company tested the process u\sing titanium oxide and made spheres measuring 1-100 nm in diameter. To overcome high-energy costs of vapor methods, NanoProducts has invented the Joule-Quench process (1-3). A mixture of raw materials is sprayed and combusted in presence of oxygen or air, followed immediately by further heating with plasma to achieve peak temperatures greater than 3,000 K. This creates hot elemental vapor that is cooled to nucleate nanoparticles, which are then quenched via Joule-Thompson expansion of the vapor stream. The sonic quenching reduces collisions between the particles and produces a stream of free-flowing nanopowders, which is filtered to harvest the nanoparticles. Shown is an SEM image of a single-phase complex of mixed metal oxide powder prepared by Five Star Technologies. The base crystallites that form the agglomerate have an average particle size of 33 nm. In another spin on vapor condensation, dubbed the "vacuum evaporation on running liquids" method, a thin film of relatively viscous liquid (e.g., an oil, or a polymer) is spread on a rotating drum. A vacuum is maintained in the apparatus, and the desired metal is evaporated or sputtered into the vacuum. Particles form in suspension in the liquid film and can be grown to a variety of sizes. 3. Solution methods - Often referred to as chemical synthesis, these methods attempt to precipitate nanoparticles from liquid precursors. This is typified by the sol-gel approach and is also used to create quantum dots (nanoparticles in which quantum mechanical properties are the key to the particles' useful behavior). The attractive feature of solution processes is their low temperature and capital costs. In addition, they arc generally better than vapor condensation techniques for controlling the final shape of the particles. Nanoparticle compositions produced using solution methods can be marketed as dry powders in the $30-300/kg range in tons-per-year volumes. Higher volumes are expected to cost less. Companies that use or have used solution methods include: * Baikowski Chemie (baikowski.com) * Cima Nanotech (cimananotech.com) * DuPont (dupont.com) * Hanse Chemie (hansechem.de) * Nanocrystals Technology (nanocrystals.com) * Nanoscale Materials (nantek.com) * Nyacol Nanotechnologies (nyacol.com) * NanoGate (nanogate.de) * Quantum Dot Corp. (qdots.com) * Sachtleben AG (sachtleben.de). A first-of-its-kind solution-phase process developed by Five Star Technologies (fivestartech.com) harnesses the energy of hydrodynamic cavitation to precipitate inorganic and organic materials in a controlled fashion, resulting in the precipitation of stable oxides containing up to four or more metals (Figure), with high phase purity (e.g., La^sub 0.8^Sr^sub 0.2^FeO^sub 3^). Called controlled flow cavitation (CFC), the process is readily adapted to the high volume production of complex metal oxides used as catalysts and additives for advanced polymers. The component metals are homogeneously dispersed and have a uniform particle size and crystalline structure. The base crystallites measure 3-50 nm, have a high surface area, and can be processed as powders or slurries. Although solution approaches are generally low-cost and high- volume, there are drawbacks. Precursor chemicals may sinter on the nanoparticles and create unwanted surface coatings. Further, solution thermodynamics can sometimes limit the complexity of material compositions that can be manufactured cost-effectively. In addition, solution methods often produce hydroxides, which need to be filtered and then calcined at higher temperatures to yield oxides. The retention of nanoscale features and high yields during filtration and calcination can be expensive and difficult to control. Novel nanoparticle production routes As the market for nanoparticles in high-tech areas such as the computers, coatings, pigments and pharmaceuticals continues to expand, the demand for nanoparticles with well-defined sizes and/or shapes in high volumes and at low costs continues to increase. This trend is responsible for a continuous refinement of existing manufacturing technologies and for the development of novel production techniques. Recently, researchers have begun to use supercritical fluids (SCFs) as a medium for metal nanoparticle growth (4). SCF precipitation processes produce a narrow particle size distribution. Generally CO2 is used because of its relatively mild supercritical conditions, and because it is inexpensive, non-toxic, non-corrosive and non-explosive and non-flammable. A possible refinement of SCF involves the stirring of surfactants with an aqueous metal salt solution in supercritical CO2. This process leads to the formation of microemulsions, which can be viewed as potential nanoreactors for synthesizing extremely homogeneous nanoparticles. Similarly, Nanomaterials Research LLC (nrcorp.com) has realized a novel nanoreactor concept, which entails synthesizing nanoporous anodized alumina membranes. The pores serve as nanoreactors for the synthesis of nanotubes and other nanomaterials. Other novel production techniques have been reported, based on the use of microwaves, ultrasound, biomimetics (mimicking biology) and electrodeposition. For instance, Sumitomo Electric (sumitomo.com) has recently developed an electrodeposition process in which metallic ions are dissolved in an aqueous solvent that is subsequently reduced to produce metallic nanoparticles. Some bacteria have been found to create magnetic nanoparticles, and bacterial proteins have been used to grow magnetite in laboratories. Yeast cells can create cadmium sulfide nanoparticles. More recently, researchers in India found a fungus capable of making gold nanoparticles, while others in the U.S. used viral proteins to create silver nanoparticles with interesting and well-formed shapes (4). Biography TAPESH YADAV is the founder and chief executive officer of NanoProducts Corp. (14330 Longs Peak Court; Longmont, CO 80504; Phone: (970) 535-0629; Fax: (970) 535-9309; E-mail: tapesh@nanoproducts.com). Before founding NanoProducts in 1994, Yadav led the fullerene and carbon nanotube business at Materials and Electrochemical Research Corp., where he participated in forming a strategic alliance with Mitsubishi (Japan). To date, he has over 40 patents pending in nanomaterials and related nanotechnology applications. Yadav has a BS in chemical engineering from MT Delhi, a PhD in chemical engineering from the Massachusetts Institute of Technology and an Associate's degree in finance from the Sloan School of Management.