is a freelance medical writer in Mamaroneck, NY.
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Nanotechnology involves materials in the 1–100 nm size range, at which they frequently acquire novel properties not seen in larger particles. Nanomaterials are already being used in commercial products, including semiconductors, research reagents, and drug delivery formulations. The potential applications have not been even partially exploited, nor has the potential toxicity of nanoscale materials been adequately investigated.
NanodetectionEric Stern is finishing his graduate work at Yale University, New Haven, CT, where he has focused on designing and building nanoscale chemical and biological sensors. The project has been funded in part by the Defense Advanced Research Projects Agency (DARPA) of the U.S. Department of Defense (DOD). “The real excitement of nanoscale sensors is that the sensing can be done labelfree and more inexpensively,” says Stern. “I hadn't seen anything like this. The way the technology existed, it took exceptional technical skill to reproduce. The coolest and most fun thing was that we got to assemble an array of people with different skill sets to realize one goal. The collaboration was the most important aspect.” He has been working with collaborators in Yale's Institute of Nanoscience and Quantum Engineering to develop nanowires that are on the same size
scale of the molecules they detect. The only way to sell the nanoscale sensor technology, Stern believes, is to excite people about its potential applications. Its real potential is that it will provide a general platform for detection that can be used anywhere by anyone. “It will take everyone a while to embrace the technology. People need to see it not as an exotic technology, but as a way to sense things, but without having to deal with labels,” he observes. Although he has no idea of the time line, he believes that the devices will be produced on an industrial scale in the not-too-distant future. Clinical and basic research applications will probably come first because their requirements will be less robust than those for military applications, the original focus of his funding.
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Tarek Fahmy, Assistant Professor of Biomedical Engineering, who like Stern, is a member of Mark Reed's group at Yale, is working on a practical application of nanowire sensors. His laboratory focuses on designing biomaterials to detect and target cells of the immune system. “The immune system is responsible for many disease states,” Fahmy notes. “If it doesn't recognize mutations, cancer can result. If it recognizes the body's own cells inappropriately, immune disease results.”
Fahmy wondered what the nanowires Stern was working on could be used for. He found it intriguing that they could detect small amounts of protons, and therefore pH changes, in 7–10 µL volumes of fluid in a highly sensitive manner. Fahmy reasoned that since one of the first responses of T cells to foreign antigens they recognize (T cell activation) is secretion of acid into extracellular fluid, it ought to be possible to detect immune T cells triggered by a foreign antigen using the nanowire technology. “If it works,” he suggests, “you could take a drop of blood, add a tumor antigen, and diagnose cancer.” They have had success detecting tumor antigen-specific reactions in seconds in samples of 200 or fewer cells.
“Because it's electronic, it could be translated to a hand held device and used to diagnose a wide range of things,” Fahmy says. Nanotechnology and microfluidic-based point-of-care diagnostic devices have been predicted for several years, and Fahmy thinks that now the nanowire technology makes it amenable to manufacture and multiplexing. Diagnostic targets in addition to cancer include infectious agents. “The great thing about it is that current diagnostics require patients to have developed cancer to a sufficient degree to biopsy, whereas the technology we are developing may be sensitive enough to make an initial diagnosis at an earlier phase of disease as well as to be used to monitor treatment.” Although some cancer antigens are well-defined and can be tested in this system, others remain to be discovered. Initial plans with collaborators include testing for one well-characterized tumor antigen in a drop of blood from a sample of patients. Multiplexing the device will come later.
Safety ConcernsStephen M. Roberts is Professor and Director, Center for Environmental and Human Toxicology, University of Florida (UF) College of Veterinary Medicine, Gainesville, FL, and is a member of the Nanotoxicology Group, a small, interdisciplinary group of UF faculty and students that is looking at potential adverse effects of nanotechnology products on human health and the environment. Although the effects of many of the components used in nanotechnology, particularly metals, are well-known, when these materials are reduced to nanoparticle size, they take on new properties that can facilitate absorption through the skin and uptake into cells and that alter their biologic effects in unknown ways. Scott Wasdo, who is also at UF and collaborates with Roberts and other investigators in the Nanotoxicology Group, is studying dermal penetration of nanoparticles. Normally the skin serves as a barrier to the absorption of many compounds encountered in the environment. However, the permeability of the skin nanoscale material is not known, and the small size of nanoparticles could allow them to move through spaces between cells in the outer layers of skin.
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“Lots of people on campus are interested in the biologic and chemical applications of nanotechnology,” Roberts says “We are trying to understand the adverse impact and perform meaningful assessments of safety. There are unique wrinkles and hurdles in using nanomaterials and the toxicology community is trying to sort them out. One dilemma is obtaining reliable and reproducible material to work on in suitable quantities.”
Nanomaterials have unique chemical and physical properties. Although exciting to work with, Roberts observes, when they aggregate or come in contact with biologic materials, nanoparticles may assume other properties. “It's easy to express a dose of a chemical, but with nanoparticles it's not clear what a dose is. Do you quantify using mass, surface area, or some other property? Some materials seem to scale with surface area, but other properties may be involved,” Roberts notes.
There are other technical issues for toxicology studies. Some nanomaterials derived from the days when the field was primarily the purview of the semiconductor industry contain heavy metals and other compounds known to be toxic (e.g., cadmium). Roberts notes that the cadmium may or may not leach out of the particles, depending on the coating. “How do you follow the particles in the body?” he asks. For animal studies like those of “classic” chemicals, where individual tissues are examined, one needs to assume particle size matters. To see the particles, electron microscopy (EM) is necessary. “Tedious doesn't begin to describe sorting through images to find and see nanoparticles in tissue, and the particles have to be electron dense. You can go nuts looking through standard EM images,” Roberts observes. Fluorescent tags may make nanoparticles easier to find, but may alter particle properties.
Future DirectionsAlthough the U.S. National Institutes of Health (NIH) has been slow to provide funding opportunities for studying the safety of nanotechnology, Roberts says, other federal agencies are involved in solicitations, including the National Institute for Occupational Safety and Health (NIOSH), the Environmental Protection Agency (EPA), and the National Institute of Environmental Health Science (NIEHS). In January, public input was invited at the National Nanotechnology Initiative's (NNI) Public Meeting on Research Needs related to the Environmental, Health, and Safety Aspects of Engineered Nanoscale Materials. Clayton Teague, Director of the National Nanotechnology Coordination Office, which organized the meeting on behalf of the Nanoscale Science, Engineering, and Technology Subcommittee on Technology, National Science and Technology Council says that they are coordinating the efforts of numerous research agencies and are looking for ways to collaborate with industry and with other countries. NNI includes 25 federal agencies, of which about half have a research and development budget for nanotechnology.
Roberts expects that ex vivo diagnostics and other applications will have a much quicker path to utility than in vivo applications (e.g., use to detect sentinel lymph nodes to assess metastasis of a primary tumor). “We hope to do something more generalized and far-reaching than just toxicology testing. We want to understand what contributes to the toxic effects and establish general principles of how things act,” Roberts says. “Size changes properties in ways we can't predict and we're trying to help people get beyond that.”
