VEPACHEDU EDUCATIONAL FOUNDATION
Provisional Application (Contd.)
Since June 8, 1995, the United States Patent and Trademark Office (USPTO) has offered inventors the option of filing a provisional application for patent which was designed to provide a lower-cost first patent filing in the United States and to give U.S. applicants parity with foreign applicants under the GATT Uruguay Round Agreements.
A provisional application for patent is a U. S. national application for patent filed in the USPTO under 35 U.S.C. §111(b). It allows filing without a formal patent claim, oath or declaration, or any information disclosure (prior art) statement. It provides the means to establish an early effective filing date in a non-provisional patent application filed under 35 U.S.C. §111(a). It also allows the term "Patent Pending" to be applied.
A provisional application for patent (provisional application) has a pendency lasting 12 months from the date the provisional application is filed. The 12-month pendency period cannot be extended. Therefore, an applicant who files a provisional application must file a corresponding non-provisional application for patent (non-provisional application) during the 12-month pendency period of the provisional application in order to benefit from the earlier filing of the provisional application. In accordance with 35 U.S.C. §119(e), the corresponding non-provisional application must contain or be amended to contain a specific reference to the provisional application.
Once a provisional application is filed, an alternative to filing a corresponding non-provisional application is to convert the provisional application to a non-provisional application by filing a grantable petition under 37 CFR §1.53(c)(3) requesting such a conversion within 12 months of the provisional application filing date.
However, converting a provisional application to a non-provisional application (versus filing a non-provisional application claiming the benefit of the provisional application) will have a negative impact on patent term. The term of a patent issuing from a non-provisional application resulting from the conversion of a provisional application will be measured from the original filing date of the provisional application.
By filing a provisional application first, and then filing a corresponding non-provisional application that references the provisional application within the 12-month provisional application pendency period, a patent term endpoint may be extended by as much as 12 months.
The later-filed nonprovisional application claiming the benefit of the provisional application must include at least one claim particularly pointing out and distinctly claiming the subject matter which the applicant regards as the invention. See 35 U.S.C. 112, 2nd paragraph. Although a claim is not required in a provisional application, the written description and any drawing(s) of the provisional application must adequately support the subject matter claimed in the later filed nonprovisional application in order to benefit from the provisional application filing date. Therefore, care should be taken to ensure that the disclosure filed as the provisional application adequately provides a written description of the full scope of the subject matter regarded as the invention and desired to be claimed in the later filed nonprovisional application. Additionally the specification shall disclose the manner and process of making and using the invention, in such full, clear, concise and exact terms as to enable any person skilled in the art to which the invention pertains to make and use the invention and set forth the best mode contemplated for carrying out the invention. See 35 U.S.C. 112, 1st paragraph.
Filing Date Requirements
The provisional application must be made in the name(s) of all of the inventor(s). It can be filed up to one year following the date of first sale, offer for sale, public use, or publication of the invention. (These pre-filing disclosures, although protected in the United States, may preclude patenting in foreign countries.)
A filing date will be accorded to a provisional application only when it contains:
Cover Sheet: Form PTO/SB/16, available on the printable forms page of the USPTO website at www.uspto.gov/web/forms/sb0016.pdf, may be used as the cover sheet for a provisional application.
Fees are subject to change annually. The current fee for a provisional application for patent can be found on the fee page (see 37 CFR 1.16(k)). USPTO Contact Center Division (UCCD) customer service representatives are available Monday through Friday (except Federal holidays) at 800-786-9199 to provide fee information. Payment by check or money order must be made payable to "Commissioner for Patents". Mail the provisional application and filing fee to:
Commissioner for Patents
Alexandria, VA 22313-1450
A provisional application automatically becomes abandoned when its pendency expires 12 months after the provisional application filing date by operation of law. Applicants must file a non-provisional application claiming benefit of the earlier provisional application filing date in the USPTO before the provisional application pendency period expires in order to preserve any benefit from the provisional-application filing.
Beware that an applicant whose invention is "in use" or "on sale" (see 35 U.S.C. §102(b)) in the United States during the one-year provisional-application pendency period may lose more than the benefit of the provisional application filing date if the one-year provisional-application pendency period expires before a corresponding non-provisional application is filed. Such an applicant may also lose the right to ever patent the invention (see 35 U.S.C. §102(b)).
Effective November 29, 2000, a claim under 35 U.S.C. 119(e) for the benefit of a prior provisional application must be filed during the pendency of the non-provisional application, and within four months of the non-provisional application filing date or within sixteen months of the provisional application filing date (whichever is later). See 37 CFR 1.78 as amended effective November 29, 2000.
Independent inventors should fully understand that a provisional application will not mature into a granted patent without further submissions by the inventor. Some invention promotion firms misuse the provisional application process leaving the inventor with no patent.
The Inventors Assistance Center (IAC) provides patent information and services to the public. The IAC is staffed by former Supervisory Patent Examiners and experienced Primary Examiners who answer general questions concerning patent examining policy and procedure. Send e-mail to: email@example.com. For additional copies of this brochure, or for further information, contact the USPTO Contact Center.
This information is general in nature and is not meant to substitute for advice provided by a patent practitioner. Applicants unfamiliar with the requirements of US patent law and procedures should consult an attorney or agent registered to practice before the USPTO.
A list of attorneys and agents can be searched at the USPTO Web site at http://www.uspto.gov/web/offices/dcom/olia/oed/roster/index.html and examined without charge at Patent and Trademark Depository Libraries (PTDLs).
A printed list is available from the US Government Printing Office at:
Superintendent of Documents (SuDocs)
P. O. Box 371954
Pittsburgh, PA 15250-7954
For information or to order by telephone call 202-512-1800. The SuDocs Web site is at www.gpoaccess.gov/index.html.
Indian drug maker Sun Pharmaceutical Industries Ltd. has reached an agreement with U.S.-based Women's First Healthcare to buy three drug-brands for $5.4 million. The brands were antibacterial Bactrim, gynaecological Ortho-Est and antimigrane drug Midrin, which have combined U.S. annual sales of $7.6 million.
Loratadine and Pseudoephedrine
Ranbaxy Pharmaceuticals, Inc. ("RPI"), a wholly-owned subsidiary of Ranbaxy Laboratories Limited ("RLL") of New Delhi, India, announced that RLL has received approval from the U. S. Food and Drug Administration to manufacture and market Loratadine and Pseudoephedrine Sulfate Extended Release Tablets, 10 mg/240 mg (24-Hour Formulation). The Division of Bioequivalence has determined Ranbaxy's Loratadine and Pseudoephedrine Sulfate Extended Release Tablets, 10 mg/240 mg (24-Hour Formulation) to be bioequivalent to the listed drug, Claritin-D(R) 24-Hour Extended Release Tablets of Schering Corporation. Total sales of $64.5 million (IRI - MAT: July 2004) were achieved for this product, sold in the OTC market.
Loratadine and Pseudoephedrine Sulfate Extended Release Tablets, 10 mg/240 mg are indicated for the temporary relief of symptoms due to hay fever or other upper respiratory allergies, nasal congestion, runny nose, sneezing, itchy and watery eyes, and itching of the nose or throat. The combination also reduces swelling of nasal passages, temporarily relieves sinus congestion and pressure, and temporarily restores freer breathing through the nose.
Nanotechnology is simply the science of small things. Nanotechnology today has become a unifying force; it cuts across disciplines and the convergence of multiple fundamental disciplines including electronics, chemistry, material science and biochemistry. Nanotechnology is essential for chip companies if we are to continue the revolution in computer hardware beyond the next decade. The uninterrupted progression of miniaturisation in semiconductor technology, that is currently hovering at the 65 to 90 nanometers nodes for electronic design is possible only through nanotechnology. It will also facilitate fabrication of entirely new generation of products that are cleaner, stronger, lighter and more precise. The ability to pack more power, performance, reliability and cost effectiveness into smaller and smaller chips can continue to revolutionise the electronics industry with better and better finished products.
See for more on The Ups and Downs of Nanobiotech: http://www.the-scientist.com/yr2004/aug/feature_040830.html
The Ups and Downs of Nanobiotech
Balance is hard to find as researchers, investors, and environmentalists jockey for position | By Jeffrey M. Perkel
Ten years from now, a visit to the doctor could be quite different than it is today. How different? Imagine tiny particles that "cook " cancers from the inside out; "smart bomb" drugs that detonate only over their targets; and finely structured scaffolds that guide tissue regeneration.
But it's not just imagination. In academic labs, small startups, and giant pharmaceutical companies, researchers in the blossoming field of nanotechnology have shown that these concepts can work -- at least in lab animals and tissue culture dishes. Now they are working to turn these proofs-of-principle into approved therapies. But a lot can happen between mouse and man, and many a "proven " therapy has failed to make the transition.
Nanotech actually is bigger than medicine, of course; those in the know say it will transform every industry. Eager to get in the act, governments and private firms worldwide have lavished the sector with cash, an estimated $8.6 billion (US) in 2004, according to one report.1 "We're seeing nanotech as a metaphorical worldwide poker game, where all of these countries are anteing up more and more money to go towards nanotech research," says Robert Paull, managing partner and cofounder of Lux Capital, a venture capital firm based in New York. And it's still anybody's game, Paull added in a followup e-mail: "The flop is on the table and countries are trying to determine what their strengths are."
But for all that, nanotechnology, which exploits the unique behavior and properties of materials on the nanometer (10 -9 m) scale, still has a long way to go. Aside from a few consumer oddities, such as stain-resistant fabrics, most companies won't have commercial nanotech products for years. And it will be decades, says Tom Theis, director of physical sciences at IBM Research, before any nanotech startup will play at the level of the Intels, IBMs, or Microsofts of the world.
Engineering hurdles are not the only obstacles. Researchers also must address the public's environmental, toxicological, and health concerns. Nanobiotech's benefits -- enhanced drug solubility and the ability of particles to enter cells, cross membranes, and cross the blood-brain barrier -- could be its undoing. "Any time you put a material into something as complex as a human being, it has multiple effects," says James Baker, director of the Center for Biologic Nanotechnology at the University of Michigan, Ann Arbor.
Eager to avoid an antinano backlash, researchers have completed scattered toxicology studies, and initiated still more. A cohesive picture has yet to emerge, but for the first time, safety data may actually guide product development. In the meantime, many advise prudence. Recent reports from Swiss Re, a reinsurance company, and the UK's Royal Society and Royal Academy of Engineering, independently urge caution in working with nanoparticulates until safety research can be conducted.2,3 The Canadian watchdog ETC Group goes even further, requesting a moratorium on nanoscience research until potential risks can be assessed.
Most experts agree such a move is both unwarranted and unlikely. What is likely, though, is that toxicology programs will derail some promising nanomaterials as they near the clinic. "What we need to do now, " says John Bucher, deputy director of environmental toxicology at the National Institute of Environmental Health Sciences (NIEHS), "is to figure out what the characteristics of those are that are likely to be harmful."
THERAPEUTICS A number of nanobiotech companies have directed their energies towards the therapeutics market. Houston-based C Sixty Inc., for instance, focuses on nanomaterials called fullerenes. Hollow shells comprising 60 carbon atoms, fullerenes (or buckyballs) have several medically relevant properties. Most notably, "Fullerenes turn out to be very, very potent intracellular and extracellular antioxidants, " says company president Russ Lebovitz.
Several neurodegenerative diseases, as well as normal aging processes, stem in part from oxidative injury. But as fullerenes are not normally biocompatible, C Sixty is tweaking their structure to develop the "next generation of small-molecule antioxidants," says Lebovitz. The company recently entered into an agreement with Merck & Co. to develop such drugs. Lebovitz says human trials are at least two years away.
Two companies, Nanospectra Biosciences of Houston and Triton BioSystems of Chelmsford, Mass., are developing anticancer therapies based on thermal ablation. Central to both companies' strategies are metallic nanoparticles activated by an exogenous energy source to heat and destroy the surrounding tumors.
Nanospectra's platform relies on nanometer-scale particles called nanoshells. With a gold shell surrounding an inert silica core, these nanoshells can be tuned to absorb or reflect light of various wavelengths depending on the thickness of the core and shell. Nanospectra's particles absorb near-infrared light that easily penetrates tissue. Triton employs targeted, polymer-coated iron oxide nanoparticles and an alternating magnetic field.
Both strategies have pros and cons. Gold nanoshell therapy implementation requires no expensive equipment. But it also requires direct line-of-sight from the laser to the tumor; it is ineffective against some tissues, such as bone; and it loses efficiency with tissue depth, though this can be overcome somewhat using fiber-optic lasers. Magnetic energy, in contrast, is unaffected by tissue, says Triton CEO Samuel Straface. "It sees tissue no differently that it does air; we can activate the particles anywhere in the body at any depth." But the patient also must lie between two magnetic poles, and whole-body treatment could be problematic if the particles accumulate in undesirable locations.
Nevertheless both approaches have shown early promise. Sally J. DeNardo and colleagues from the University of California, Davis, Medical Center presented evidence at the Society of Nuclear Medicine's annual meeting that Triton's nanoparticles, coupled to a monoclonal antibody specific for epithelial cancers, slowed the growth of a human breast cancer xenograft in nude mice. 4
Nanospectra, meanwhile, has demonstrated complete tumor destruction using its gold nanoshells.5 "All of the tumors had completely regressed within 10 days, and even now, a year later, the mice are still alive with no regrowth of the tumors whatsoever," says Nanospectra cofounder Jennifer West, a professor of bioengineering and chemical engineering at Rice University in Houston. The company plans to initiate human clinical trials for the treatment of mesothelioma in 18 months; Triton hopes to start its own trials in 2006.
DRUG DELIVERY In the drug-delivery arena, companies are developing approaches to encapsulate drugs to minimize side effects, increase bioavailability, and enhance solubility. According to Paull, roughly 28 drugs are coming off patent in the next five years, representing some $46 billion in lost revenues to the patent owners. One way to extend a patent's effective lifetime is to reformulate an existing drug. "Nanotechnology is one of a few areas that [the drug industry is] really focusing on to do that," he says.
Elan Pharmaceuticals' NanoCrystal technology helps pharma companies improve drug solubility. At present two commercial products use NanoCrystal technology, Wyeth's Rapamune and Merck's Emend. But Dublin-based Elan recently announced it had licensed the technology to Roche for one of that company's drug candidates, and additional product launches are expected in the next few years.
Flamel Technologies of Lyon, France, uses its Medusa platform for drug encapsulation. According to Flamel's Web site, Medusa is a "self-assembled, polyamino acid nanoparticles system." The amphipathic material encapsulates protein drugs in a latticework of protein and carrier, which slowly breaks apart upon injection, delivering the drug slowly over time. The company's human insulin formulation, called Basulin, for instance, remains active in the blood for 24 hours after injection, according to Flamel's Web site. The company has entered into an agreement with Bristol-Myers Squibb Company to market and develop the drug.
Another encapsulation approach involves nanomaterials called dendrimers. A dendrimer is basically like an onion, says Donald Tomalia, president and chief technical officer at Dendritic NanoTechnologies, Mt. Pleasant, Mich. "It has an information-bearing core that defines the nature of the shell or the onion layers that you put around it, " says Tomalia. Like an onion, dendrimers grow from the inside out, layer-by-layer, growing 1 nm in diameter with each generation.
Dendritic Nanotechnologies is working to encapsulate anti-cancer drugs such as cisplatin inside the dendrimer's hollow interior, using a surface-bound targeting molecule to direct the complex to its intended target. Another dendrimer company, NanoCure, covalently attaches drug molecules to the dendrimer surface along with a targeting moiety.
Though NanoCure founder, James Baker says the company is at least two years away from human trials, dendrimers are working their way toward the clinic. Dendrimers covalently coupled to gadolinium make an effective contrast agent for magnetic resonance imaging, says Tomalia. "They have been used in vivo in animals for about 10 years with virtually zero side effects," he says. This past January Australian drug developer Starpharma initiated a Phase I human clinical trial of its VivaGel formulation, a dendrimer-based topical microbicide for the prevention of HIV, herpes, and other sexually transmitted viral diseases.
TISSUE RECONSTRUCTION Another area being served by nanotech is tissue reconstruction. At the Institute for Bioengineering and Nanoscience in Advanced Medicine at Northwestern University, Chicago, director Sam Stupp's lab is developing self-assembling liquids that solidify upon injection. This tissue then forms structured scaffolds that present ordered biological signals (i.e., peptides) to cells.
Key to this material are long cylindrical nanofibers 6-8 nm in diameter and composed of peptide amphiphiles that aggregate noncovalently. In February Stupp's team demonstrated that one such scaffold could induce selective differentiation of neural progenitors into neurons, as opposed to astrocytes, a finding that ultimately could lead to a therapy for otherwise paralyzing central nervous system injuries.6 Other focus areas for Stupp's team include islet transplantation and bone regrowth.
"I think regenerative medicine is where nanotechnology will flourish," says Stupp. "Now nanotechnology is expensive, and so you have to solve extremely important problems with it. I think reversing paralysis or blindness is an example of something that deserves an expensive technology."
DIAGNOSTICS AND IMAGING Diagnostics are perhaps as important as therapies. Northbrook, Ill.-based Nanosphere is using its Verigene nanotech platform to develop an accelerated test for methicillin-resistant Staphylococcus aureus. Standard protocols for MRSA can take 48 to 72 hours, says Vijaya Vasista, chief operating officer. "What we have in development is an assay that would take about an hour after the initial culture, and the next-generation assay will be directly from the sample."
Nanosphere builds molecular diagnostics modeled on sandwich-type assays. Surface-bound oligonucleotides capture specific target nucleic acids, which in turn capture oligonucleotide-bearing gold nanoparticles. Particle size is critical to their stability, says Vasista. The resulting complexes can be detected by a silver precipitation reaction that increases the signal intensity 1,000 to 10,000 times. Vasista says the company hopes to launch its first products in early 2005.
Immunicon of Huntingdon Valley, Pa., employs a "ferrofluid," a colloidal suspension of nanoscale ferrous oxide coupled to antibodies against the epithelial cell-adhesion molecule, EpCAM. These particles help concentrate rare human epithelial cells, such as circulating cancerous cells, in blood for subsequent automated staining and analysis.
According to Carrie Mulherin, vice president of marketing, the system is sensitive enough to detect a single cancerous cell in 7.5 ml of human blood. "You can think of it as finding a grain of salt in a five-pound bag of sugar," she says. Immunicon plans to release its first in vitro diagnostic product this quarter.
Several researchers have recently used nanoparticles called quantum dots for live-animal imaging. Quantum dots are nanoscale semiconductor crystals, often of cadmium selenide or lead selenide, which exhibit tunable optical properties. By changing a crystal's diameter, it can be made to absorb and emit light of different wavelengths. But unlike organic fluorophores, each of which has a different absorption spectrum, quantum dots made from a specific material can all be excited by a single light source, making complicated fluorescence microscopy setups with multiple lasers obsolete. Quantum dots also are brighter than organic dyes, do not photobleach, and have narrow emission spectra (which makes multiplexing easier).
John Frangioni of Harvard Medical School and colleagues used quantum dots to locate "sentinel" lymph nodes through the skin of living mice (sentinel lymph nodes are often removed for cancer diagnostic screening, but they can be difficult to locate).7 "The size of the quantum dots turns out to be ideal for getting into the lymph system and then getting trapped in the sentinel lymph node," says Andy Watson, vice president of business development at Quantum Dot in Hayward, Calif.
More recently, Shuming Nie of the Winship Cancer Institute at Emory University in Atlanta and colleagues performed live-animal imaging of quantum dots targeted specifically to prostate cancer xenografts in mice.8 The team injected antibody-coupled nanoparticles into the animals' tail veins prior to imaging.
Despite these in vivo advances, quantum dots will likely find their greatest use in cultured cells and tissue specimens. They may also continue to be used in animal models, but Nie says he is not sure if they can ultimately be applied to human patients.
SAFETY CONCERNS That's because quantum dots, like all nanoparticles, pose potential human health risks. The nanotech world collectively cringed in April when Eva Oberdörster, a researcher at Southern Methodist University in Dallas, reported at the American Chemical Society's national meeting that water-soluble fullerene molecules cause brain damage in largemouth bass. The story received considerable media coverage, despite its preliminary nature and not having been peer-reviewed (it has since been published9).
Other nanoparticles also are problematic. Dendrimers can cause osmotic damage, activate the clotting and complement systems, and even rip membranes off cells, says Baker. And quantum dots, composed of metals such as selenium, lead, and cadmium, would likely be toxic to most organisms if the metal leeched out of the particles. Developers add coatings to ensure safety and stability, but Alan Waggoner, director of the Molecular Biosensor and Imaging Center at Carnegie Mellon University in Pittsburgh, demonstrated recently that the movement, retention, and distribution of quantum dots varies greatly based on these surface coatings.10
Nanoscale materials, observes the NIEHS's Bucher, "don't act like particles and they don't act like chemicals. They take on properties that are either intermediate or they are unique, and we're just beginning to sort through this." The NIEHS recently initiated a series of studies designed to address these and other issues for quantum dots, nanoparticulate titanium dioxide, and buckyballs. Led by Bucher, the studies will concentrate on three questions: How do surface coatings and chemistries affect where nanomaterials go in the body; what are the immunologic properties of these nanomaterials; and what are their toxicological effects.
PUBLIC MISUNDERSTANDINGS The results, say Bucher, can help guide product development to make them safer. But a pair of surveys conducted this year, both in the United States and in Britain, reveals a public largely ignorant of his efforts, and indeed of nanotech in general.
A nationwide survey from North Carolina State University (NCSU) in Raleigh found that more than 80% of Americans know "little" or "nothing" about nanotech.11 In the UK, a March report released jointly by the Royal Society and Royal Academy of Engineering shows that only 29% of respondents have heard of nanotech, and only 19% could offer a definition, whether accurate or not.12
On the other hand, both surveys recorded a positive attitude regarding nanotech. In the NCSU study, 40% of those surveyed believe nanotech will produce benefits exceeding risks, compared to 22% who believe the opposite was true. In Britain, 68% of those offering a definition of nanotech predicted it would improve the future, compared to 4% who said it would make things worse.
That's a sentiment echoed by those in the know, too. Says Theis: "If information technology is worth a trillion dollars a year in the economy, imagine what we're going to do when the benefits of this kind of miniaturization are extended to the life sciences and medicine, and just about every industry and ... manufactured object will incorporate this technology. How big will that be? It will be everything."
Jeffrey M. Perkel (firstname.lastname@example.org)
1. Lux Research, The Nanotech Report 2004.
2. "Nanoscience and nanotechnologies: Opportunities and uncertainties," available online at www.nanotec.org.uk/finalReport.htm
3. A. Hett, "Nanotechnology: Small matter, many unknowns," available online at www.swissre.com.
4. S. J. DeNardo et al., "111 In ChL6 nanoparticles: Development of effective tumor targeting bioprobe AMF cancer therapy," Society of Nuclear Medicine national meeting 2004, Abstract #265.
5. D. P. O'Neal et al., "Photo-thermal tumor ablation in mice using near infrared-absorbing nanoparticles," Cancer Lett, 209:171-6, June 24, 2004.
6. G. A. Silva et al., "Selective differentiation of neural progenitor cells by high-epitope density nanofibers," Science, 303:1352-5, Feb. 27, 2004.
7. S. Kim et al., "Near-infrared fluorescent type-II quantum dots for sentinel lymph node mapping," Nat Biotech, 22:93-7, 2004.
8. X. Gao et al., "In vivo cancer targeting and imaging with semiconductor quantum dots," Nat Biotechnol, 22:969-76, August 2004.
9. E. Oberdörster, "Manufactured nanomaterials (fullerenes, C 60) induce oxidative stress in the brain of juvenile largemouth bass," Environ Health Persp, 112:1058-62, July 2004.
10. B. Ballou et al., "Noninvasive imaging of quantum dots in mice," Bioconjugate Chem, 15:79-86, 2004.
11. M.D. Cobb, J. Macoubrie, "Public perceptions about nanotechnology: Risks, benefits and trust," available online at www2.chass.ncsu.edu/cobb/me/index.html.
12. "Nanotechnology: Views of the general public," available online at www.royalsoc.ac.uk
Research Vision | Sustainability for Nanotechnology
Making smaller safer and changing the way industry thinks in the process | By Vicki L. Colvin
When materials and devices are fabricated with tiny dimensions, their properties and applications expand enormously. Small size, which for nanotechnology means less than 100 nm, confers on devices and materials enhanced flexibility and improved performance. We've begun exploiting such properties in a multitude of emerging areas ranging from computing to translational medicine. Yet, just as the promise of nanotechnology becomes more defined, skeptics raise questions about the unforeseen risks this new technology may present for the environment and our health.1,2
For once, these concerns are not falling on deaf ears. Many in the scientific enterprise have learned, from examples such as DDT and genetically modified organisms, that ignoring reasonable fears and concerns about emerging technologies can halt or even derail technology's progress. Industry now appreciates the costs of neglecting risks posed by new chemicals, materials, or devices.
I also find personal reasons for taking nanotechnology critiques seriously. Nanotechnology has received an unprecedented level of government and public support based in large part on speculations about its benefits. Just as I work to realize these positive visions, I feel some obligation to give equal time to evaluating speculations on potential risks. Yet whatever the reasons, nanotechnology stakeholders ranging from governments to universities have engaged in defining its environmental and health risks.3
They are not starting from scratch. Nanotech may be new, but it rests on a large and extensive body of knowledge concerning the production and biological properties of naturally occurring and waste nanoparticles. At least in pulmonary toxicology, it is well established (through animal studies) that exposure to ultrafine particles through inhalation is best avoided. We don't know yet whether a similar rule will hold for manufactured, or so-called engineered, nanoparticles. While these systems share the minute size with many hazardous ultrafine particles, their purity, exposure pathways, and levels are known to be very different (see table above). How these differences will manifest remains a subject of great interest.
NANO EXPOSURE More than 500 years ago one of the first toxicologists, Paracelsus, said, "The dose makes the poison." Clearly, the exposure of an organism to a substance is at least as important as its biological effects when measuring overall risk. A discussion of engineered nanomaterial risk must then begin by examining exposure issues.
Currently the average person faces virtually no exposure to nanoparticles and thus little risk. While there are many manufacturing plants under construction, commercial technologies for most nanoparticles are several years away. High cost precludes widespread application in bulk consumer products, and I estimate that for engineered nanoparticles such as fullerenes, quantum dots, and metal nanocrystals, the total global production is less than one ton. (The term engineered nanoparticle as yet lacks a formal definition. Some colloidal particles, such as carbon black, fused silica, or pigments in cosmetics and sunscreens, may have dimensions of less than 100 nm. For the purposes of this article, I am limiting my discussion to more modern materials with tunable properties and high molecular control). These substances thus currently pose little risk to public health. Nevertheless, the substantial investment in nanotechnology research and manufacturing by governments and industry alike suggests a budding industry poised to expand over the next 10 years. Accurately identifying environmental and health risks arms this new industry with the information needed to ensure good stewardship and product sustainability.
Initial information concerning nanoparticle exposure issues suggests that environmental processes such as bioaccumulation, biodegradation, fate, and transport will have significant effects on the local concentration and form of engineered nanomaterials. On one hand, nanoparticles may be less mobile in groundwater systems than larger particles. The high surface areas of these materials maximize chemical interactions with porous media so that even relatively noninteracting particles experience slow transport through pores. On the other hand, the high surface areas of engineered nanoparticles can lead to significant adsorption of molecular contaminants. In one case, hydrophobic contaminants irreversibly interacted with fullerene aggregates in water, and these species showed a high capacity for concentrating a model polyaromatic hydrocarbon.4 Thus, while engineered nanoparticles may be less mobile than larger particles, their higher surface areas could concentrate hydrophobic molecules.
BIOLOGICAL EFFECTS In considering nanoparticles' effects on organisms, the most compelling feature is physical size. With dimensions of less than 100 nm and more typically less than 10 nm, these materials have in principle wide access to biological systems. In practice, however, engineered nanoparticles are prone to aggregation in biological systems, producing much larger particles that lack the solubility and mobility of isolated materials. Such aggregation problems confounded pulmonary toxicology studies designed to evaluate the effects of single-walled carbon nanotubes on rodents.5 Indeed, great effort must be expended in designing appropriate surfaces to resist aggregation. Still, with appropriate derivatization, engineered nanoparticles access even the smallest biological compartments within human cells.
Another consequence of their small size is that for a constant weight, a sample will contain many more nanoparticles than an equivalent micron-sized material. In pulmonary toxicology, this property has been suggested to result in macrophage overload, in which cells responsible for clearing foreign particles become overloaded by the sheer number of particles requiring clearance.6 This can result in enhanced inflammation and in some cases translocation of aerosolized nanoparticles to the central nervous system and the olfactory bulb.7
Whether engineered nanoparticles can be aerosolized from routine handling of powders and liquids is not yet known. One study found no respirable levels of small nanoparticles in a variety of workplaces that processed the materials. Rapid and irreversible aggregation of engineered nanoparticles in air may increase their mean size significantly and thus limit the inhalation exposure of organisms to isolated nanoparticles.
For those engineered nanoparticles that retain their small size in biological systems and are resistant to aggregation, it is likely they will be widely distributed in most organisms. Many engineered nanomaterials are designed to be chemically active, and in those cases exposures will result in unique and in some cases unwanted biological properties.8 However, it is typically straightforward to render nanostructures chemically inert; in the case of C60 such a treatment can change its cytotoxicity many orders of magnitude (Figure 1).9,10 These data illustrate that for nanomaterials, the core composition of a material may be only a small component in defining its toxicity. Far more critical will be how the surface chemistry controls aggregation, bioavailability, and the subsequent reactivity of the nanoparticles.
IMMEDIATE RELEVANCE Because the industry is in its infancy, limited exposures to people and the environment of engineered nanomaterials mean that this area is not of immediate importance to public health. Still, rapid growth coupled with the existing data concerning ultrafine particles does make the question immediately relevant. Significant strides are being made in answering this question, and over the next few years an explosion of technical data will appear in this area, which will equip nanotechnologists for the future.
While these data are certain to transform nanotechnology, the greater impact may be on the general process of technology assessment. Traditionally, risk assessment begins when the source of a contaminant and its exposure pathways are well known. From this starting point a multitude of possible outcomes and their risks can be calculated. Clearly for nanotechnology this process must expand to include a wider range of "what-if" scenarios for possible products, nanomaterials, and exposure routes. All these factors will lead to more general risk assessments with less accurate risk projections. If the nanotechnology industry can benefit from these more general and less quantitative models, then future technologies may approach risk assessment in a new way.
Nanotechnology also provides a new model for how scientists and engineers should manage the technical issues associated with technology's risks. In the past, technologies experienced their environmental and health considerations as downstream hurdles for nearly mature products. Now, toxicologists and environmental engineers are integrated into the nanomaterials engineering process; rather than being gatekeepers, they enable chemists like myself to design biocompatible nanostructures and manufacturing processes with minimal environmental impact.
Safety and sustainability are no longer problems that concern only end-users well after the field is commercialized. Instead, they are flexible parameters in a new, and I think wiser, technology-design process.
Vicki L. Colvin is a professor of chemistry and chemical
engineering at Rice University and also director of the NSF-funded Center
for Biological and Environmental Nanotechnology, which addresses nanotech's
health and environmental impact. Her research focuses on developing and
applying new nanomaterials to solve problems in environmental and biomedical
technologies. She has received numerous awards including an Alfred P. Sloan
Research Fellowship and the Camille Dreyfus teacher-scholar prize.
1. "Nanoscience and nanotechnologies: opportunities and uncertainties," 2003, available online at www.nanotec.org.uk/finalReport.htm
2. A.H. Arnall, "Future technologies, today's choices," Greenpeace Environmental Trust, 2003, as well as various reports from the ETC group, available online at www.etcgroup.org
3. As an example, see ongoing research at the US research center, CBEN (www.rice.edu/cben) or at the EC consortia, Nanosafe (www.nanogate.com), and www.dechema.de/data/dechemaneu_/Presse/PM Nanosafe-eng.pdf
4. X. Cheng et al., "Naphthalene adsorption and desorption from aqueous C60 fullerene," J Chem Eng Data, 49:657-83, 2004.
5. D.B. Warheit et al., "Comparative pulmonary toxicity assessment of single-wall carbon nanotubes in rats," Toxicol Sci, 77:117-25, January 2004.
6. K. Donaldson et al., "Ultrafine particles: Mechanisms of lung injury," Phil Trans Roy Soc Lond, 358:2741-9, 2000.
7. G. Oberdörster et al., "Translocation of inhaled ultrafine particles to the brain," Inhal Toxicol, 16:437-45, June 2004.
8. E. Oberdörster, "Manufactured nanomaterials (fullerenes, C60) induce oxidative stress in the brain," Environ Health Perspect, 112:1058-62, July 2004.
9. V.L. Colvin, "The Potential environmental impact of engineered nanomaterials," Nat Biotechnol, 21:1166-70, 2003.
10. C.M. Sayes et al., "Investigating the differential cytotoxicity of nanoscale water soluble fullerene species," Nanoletters, in press, August 2004.
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