Still in its infancy, research and development at the nanoscale has already made an impact. Yet roadblocks to commercialization still exist.


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mages: Simultaneous ETEM observations using high-resolution imaging (HRTEM), electron diffraction (ED), and electron energy-loss spectroscopy (EELS) demonstrate changes in physical and electronic structure of ceria catalyst particles in a reactive hydrogen environment as the temperature increases from 600 C to 730 C. (Ultramicroscopy 108 (2008) 1432– 1440, 2008)   

Nanotechnology typically describes any material, device, or technology where feature sizes are smaller than 100 nanometers in dimension. However, this new and uncharted direction in research provides a large spark for new product and drug delivery development. To achieve these discoveries, scientists must rely on specialized instruments and materials to drive their experiments and analysis.

R&D Magazine surveyed leading instrument and materials vendors to gauge their opinion on nanotechnology’s growth and the challenges this science faces.

Nanotech trending
As researchers began working in nanoscale domains, most efforts focused on characterizing materials and understanding the relationships between their structure (composition) and properties. As scientists improved their understanding of these structure-property relationships, “their focus shifted to relationships between structure and function,” says Jens Greiser, VP/CTO, FEI Co., Hillsboro, Ore. To achieve this, microscopy and instrument vendors realized they would first have to make it easy to see structures at the atomic scale. For example, transmission electron microscopes (TEMs) have been used for years to characterize the size and shape of nanoparticles, but until aberration-corrected optics became commercially available, TEM could not clearly visualize atomic structures at the particle surface. With this added analytical capability, researchers could begin to establish a relationship between the structure of a nanoscale feature and its properties and function.

While characterization tools have strengthened, so have the actual use of nanomaterials. Over the past several years, some of the most dramatic advances in nanotechnology have come from new applications resulting from the development and modification of nanoscale-enhanced materials; thus the trend of movement from conceptual nanoengineered products to real-world applications.

The semiconductor industry has manufactured nanoscale features for many years, but beyond this industry many commercial nanotechnology-enabled products have integrated nanomaterials as passive components.

“Another trend is the transition from passive to active devices incorporating nanotechnology,” says Mike Nelson, CTO at NanoInk, Skokie, Ill. It’s been estimated, according to Nelson, that in the last decade nanotechnology has provided solutions for about 50% of new projects in energy conversion, energy storage, and carbon encapsulation. Also, in 2010, 15% of advanced clinical diagnostics and therapeutics were nanotechnology based.

Nanomedicine and energy are leading applications of nanotechnology, says Nelson, along with many of the other vendors surveyed, and represent two of the most important research areas.

Jeremy Warren, CEO, NanoSight, Salisbury, U.K., identifies an increasing emphasis on bionanotechnology as a trend he sees as the inherent complexity and heterogeneity of biological nanoparticles make increasing demands on characterization technologies. In biotechnology and life science applications, incorporation of nanoparticles as part of biosensing and drug delivery systems has taken off. Used in conjunction with biological systems, nanomaterials have applications in the early detection and treatment of various diseases, particularly cancer.

“Novel nanomarkers that can identify and visualize cancer cells can help diagnose malignancy without invasive biopsy procedures,” says Natasha Erdman, FE-SEM product manager, JEOL USA, Peabody, Mass. Metal-oxide nanoparticles can bind to antibodies that identify specific receptors and provide contrast for imaging with magnetic resonance imaging (MRI) or computed tomography (CT). Since 2010, two nanotechnology-based cancer drugs have passed regulatory scrutiny and are on the market—Doxil and Abraxane, according to the National Cancer Institute’s Alliance for Nanotechnology in Cancer. In recent years, the FDA approved numerous Investigational New Drug applications for nanoformulations, enabling clinical trials and further possibilities for nanomedicine.

Also, nanotechnology continues to find new roles in energy, from nanostructures used to make light-emitting diodes (LEDs) more efficient and enhance solar cell performance, to nanomaterials in advanced energy storage devices. Current developments involve modification of solar film structures with dopants to improve their efficiency, as well as understanding nanopore connectivity in gas shale for natural gas exploration.

“Our current research is in the area of coatings that can assist the oil and general well drilling industry,” says Brian Doud, general manager, Powdermet Inc., Euclid, Ohio. “We’ve developed antifriction and anticorrosive materials that can be applied to the inside of oil well pipe before they’re sold to the drilling company. These materials can take the heat and rigor of the drilling process, while extending the life of the down-hole pipe and improving the safety of the well.”

Nanotechnology’s hand in energy
While nanotechnology use in biomedical applications has grown, some of the strongest innovations he sees in nanotechnology are related to energy storage and production, according to Erik Novak, director of advanced development, Bruker NanoSurfaces Division, Santa Barbara, Calif. “We have customers designing specialized structures that increase the capacity and durability of next-generation batteries, while others are using nanotechnology to create devices that are more energy efficient.”

The shelf life of most disposable and rechargeable batteries is relatively short, due to self-discharge after they are manufactured, even before being used in a device. mPhase Technologies, Little Falls, N.J., has created a reserve battery, called the AlwaysReady Smart NanoBattery, that eliminates this problem. The company makes their structures smaller than traditional reserve batteries by using a porous custom silicon membrane. The diameter of the membrane pores is on the micrometer scale, with nanoscale features located on the surface of each porous region. In addition, the top of the porous membrane is coated with a material that repels a liquid electrolyte. In the battery design, if liquid is poured onto the membrane, the nanostructures and materials forming the coating of the membrane repel it, suspending the liquid with a little cushion underneath it. The battery is triggered through electrowetting.

Graphene has been touted for use in battery technology due to its high surface area and high thermal conductivity. Angstrom Materials, Dayton, Ohio, manufactures nanographene platelet (NGP) material used for next-generation lithium-ion batteries, fuel cell bipolar plates, and supercapacitor electrodes. Their NGP material has one of the highest thermal conductivities known today—up to ~5,300 W/mK—or five times that of copper at a density four times lower and a surface area twice that of carbon nanotubes.

 (a) Sequential TEM images of nanopores, showing their shrinkage in a graphene sheet at 400 C and (b) Sequential TEM images of nanopores, showing their shrinkage in a graphene sheet at 800 C . Image: Moon Kim, University of Texas, Dallas“For lithium-ion battery applications, our NGPs serve as a conductive additive for both the anode and cathode of the technology,” says Ron Beech, director of marketing and sales, Angstrom Materials Inc.

Noting that catalyst research plays a large role in energy research, JEOL’s Erdman saw a connection in hollow, soft-shelled particles called “lava dots” discovered at Rice University. These materials were formed when three types of solid powders—cadmium nitrate, selenium, and a tiny amount of CTAB—were added to an oil solvent and slowly heated. The group discovered that the molten selenium wrapped around the cadmium nitrate droplet, which diffused out and left a hole. This discovery allowed the team to explore the potential use of these particles—in lieu of quantum dots—as catalysts for hydrogen production, chemical sensors, and components in solar cells.

This work in catalysts plays well into the microscope industry. FEI’s Greiser states that their Titan ETEM allows scientists to investigate changes in the structure and function of the particle surface in real time as the material responds to stimuli, such as changes in temperature, pressure, or environment. The ETEM is an environmental transmission electron microscope that enables time-resolved, in situ studies of processes and materials exposed to reactive gases and elevated temperatures.

“For example, scientists can observe changes in atomic structure at the surface of ceria catalyst nanoparticles in response to temperature changes during the catalytic oxidation of hydrogen using the Titan ETEM,” says Greiser. The ability to make these observations in an environment that mimics an actual process environment is critical to understanding the catalyst at a fundamental level.

Powdermet’s Doud notes that some of the most innovative developments in nanotechnology are taking place in the adhesives and insulation sectors. Nanomaterials enable the development of innovative chemistries and materials with extreme stickiness, as well the ability to withstand extreme heat.

“Combined, they provide capabilities for insulating processes in environments and places where no technology has been able to perform,” says Doud. “It’s now possible to protect well pipe at submersible depths exceeding 12,000 feet from the cold temperatures that exist at those depths.” This essentially allows the oil to be brought to the surface using less energy.

The world of bionanotechnology
Perhaps the most dynamic and exciting developments in nanotechnology are occurring in areas where biology and nanotechnology converge. Here the tools of nanotechnology are used to better understand biological systems, like cells, and how they operate at the nanoscale level for development of future applications.

NanoInk’s Dip Pen Nanolithography (DPN) technology is a nanofabrication technology that relies on scanning probe microscopy with nanometer scale resolution to enable users to directly pattern biomaterials with nanoscale resolution and registration in such areas as proteomics, cell biology, and biosensors. The company’s NanoBioDiscovery Division uses DPN and other instruments as nanomanufacturing systems for printing protein nanoarrays on glass slides. These protein nanoarray assays provide a solution for the detection, identification, and quantification of clinically and biologically relevant, low-abundance proteins from various sample types. By miniaturizing a protein array assay on a standard glass slide format, the system provides benefits to the end user including improved sensitivity, small sample size, and reduced reagent costs. Several large pharmaceutical companies use this system for their drug discovery and development research programs.

“We have several customers using our tools for biosensor and microstructure functionalization,” says NanoInk’s Nelson. “We can readily fabricate semiconductor-based sensor elements, such as nanowire field effect transistors, but to make them useful as biosensors each sensing element needs to be functionalized with a capture agent that binds with the target to produce a measureable signal.”

Biomedical sensors is the most common application gaining attention and driving nanotechnology, according to John Wagner, VP of business development for the GM Electronics and BIO Business Unit at Advanced Diamond Technologies (ADT), Romeoville, Ill. ADT manufactures ultrananocrystalline diamond technology for electronic, industrial, and biomedical markets. Investment in nanotechnology for implantable, diagnostic, and research tools for single-molecule sensing has grown to support a $30 billion market.

Enhancements in computing power and component miniaturization have paved the way for real-time, multistage diagnostics, and programmable drug/treatment infusion.

One biosensor application uses nanoprobes implanted on the brain to detect various chemistries, with an appropriate stimulation applied as a corrective action, says Wagner. Additional advances in communications technologies have opened the world to remote diagnosis and treatment.

The study of exosomes is where NanoSight’s Nanoparticle Tracking Analysis (NTA) technology is being used to develop early stage detection of cancers through the monitoring of diagnostic biomarkers. NTA visualizes, measures, and characterizes nanoparticles and microparticles from 10 to 2,000 nanometers.

A good example of NanoSight’s NTA application to exosomes is work published by Hector Selgas and David Lyden at Weill Cornell Medical College, who reported a breakthrough in cancer metastasis research in Nature Medicine. “The paper describes how exosomes secreted from melanoma tumor cells are educating bone marrow-derived progenitor cells toward a pro-metastatic phenotype,” says Warren. They are also interested in analyzing the use of exosomes as biomarkers for prognostic factors for specific tumor types.

High-resolution TEM images show reconstructed graphene edge structures at 1200 C. Image: Moon Kim, University of Texas, DallasResearchers have also studied the capabilities of graphene for applications related to the life sciences. JEOL’s Erdman states its potential for use in sequencing DNA was recently determined in work at the University of Texas, Dallas, where Moon Kim’s laboratory manipulated the size of a graphene pore to less than one nm. “The team tailored the size of the graphene nanopore, shrinking it in situ, by using a combination of electron beam irradiation and controlled heat,” says Erdman. Such a graphene nanoscale sensor could be integrated with electronics to make a low-cost method for DNA sequencing, enabling scientists and doctors to better predict and diagnose disease, and also tailor a drug to an individual’s genetic code.

Regulatory issues, funding, and skepticism
Concern over the potential toxicity of engineered nanoparticles has accompanied the development of nanotechnology from its earliest beginnings, but, according to Warren, the issue was brought into focus with the European Union (EU)’s publication at the end of 2011 of their definition of “nanomaterial”. This statement was merely a recommendation, but because it came from the EU and was the result of years of scientific assessment and consultation, it has been pursued by legislators.

“Despite its European provenance, the impact of this change is global as imports to the EU will be directly affected, and some sectors, notably cosmetics and food, are coordinated to bring about global harmonization,” says Warren. New standards will be required from characterization tool providers to meet the requirements of likely legislation. However, vendors are seeing more industrial stakeholders responding to this in a positive manner to better understand their own products and how nanotechnology impacts processes from raw materials to finished products and their environmental fate.

Overall, there have been a limited number of conclusive studies on the health impact of nanomaterials.

In the case of biomedical applications, the lack of resolved regulations may drive many nanotechnology companies who are addressing these applications to take their materials and concepts outside of the U.S. The reason for this is that the barrier to entry is much lower, says Wagner.

According to Nelson, the gap between invention and innovation is huge. Many scientific and technical challenges need addressing, and obtaining and sustaining the level of investment required to solve these problems represents a critical challenge for any nanotechnology venture as such research is still in early stages. Funding for nanotechnology development depends on current government agencies’ priorities and if it receives funding for materials and applications development at the university level.

However, nanocomposite materials are used in products today. These tend to be high-end products because of cost constraints, but some low-end markets are beginning to be served. Most nanomaterials are perceived as expensive and innovators may not recognize all the attributes of these unconventional materials. This brings up an economical discussion, where education is required before an R&D project can begin. According to ADT’s Wagner, due to the infancy of nanomaterials, most next-generation applications will come from new thinking and novel approaches to innovation.

Other scientific roadblocks for nanotechnology relate to the computing power and nature of instrumentation that must keep pace with the size of the materials needing characterization.

“As we move from the creation of still images to the recording of dynamic processes, the sheer volume of data produced is staggering,” says FEI's Greiser. Generation of terabytes of data in a single experiment is not uncommon. And the problem goes beyond simply recording and managing these large data sets.

“To be truly useful we must find effective ways to analyze the data to find significant relationships, visualize those structures and relationships, and model the processes,” continues Greiser. All of these require advances in computational power and analytical and modeling software.