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Grand Challenge Workshop Series

Nanotechnology Innovationfor

Chemical, Biological, Radiological, and Explosive (CBRE): Detection and Protection

Final Workshop ReportNovember 2002

in cooperation withThe AVS Science and Technology Society

About this DocumentA workshop on May 2-3, 2002, was organized by the AVS and coordinated with a meeting of theAVS Science and Technology Society held in Monterey, California on May 1 and 2, 2002. Theworkshop was supported in part by the NNCO. Selected participants in the AVS meeting wereinvited to stay an extra day at the workshop. This report summarizes the workshop determination ofthe opportunities and challenges for nanoscience and technology research as applied to the NNIGrand Challenge on Chemical, Biological, Radiological, and Explosive (CBRE) Detection andProtection.

About the CoverBioCOM chip developed at the University of California, Berkeley, based on the observation ofchemo-mechanical microcantilever beam actuation induced by biomolecular binding. The chip iscurrently being developed for high-throughput multiplexed biomolecular analysis. This chip-levelmicrocantilever array is expected to provide a quantitative, label free, and low cost platform fordetection of various biomolecules, such as DNA and proteins. This illustrates the potential fornanotechnology-based approaches to detection of and protection from chemical, biological,radiological, and explosives threats (courtesy of A. Majumdar, U.C. Berkeley).

Workshop Report

Recommended Investment Strategy

Workshop ParticipantsMay 2-3, 2002, Monterey, CA:

Dr. James Baker University of MichiganDr. Richard Colton Naval Research LaboratoryDr. Heidi Schroeder Gibson U.S. Army Natick Soldier CenterDr. Michael Grünze University of Heidelberg, GermanyDr. Stephen Lee Army Research OfficeDr. Kenneth Klabunde Kansas State UniversityDr. Charles Martin University of FloridaDr. James Murday Naval Research LaboratoryDr. Thomas Thundat Oak Ridge National LaboratoryDr. Bruce Tatarchuk Auburn UniversityDr. Keith Ward Office of Naval Research

Any opinions, conclusions, or recommendations expressed in this material are those of the workshop participants and do not necessarily reflect theviews of the participants’ home institutions or of the United States Government.

Table of Contents

Executive Summary............................................................................................................................3

I. Vision ................................................................................................................................................4

II. Relevance of Nanotechnology to CBRE Detection and Protection .....................................................4DetectionProtection

III. Nanoscience/Nanotechnology Research Opportunities ....................................................................10Short-term (1-5 yr), Mid-term (5-10 yr), and Long-term (10-20 yr) TransitionsNanoscience Opportunities for Detection: Miniaturized, Intelligent Sensors (MIS)Nanoscience Opportunities for Protection/Remediation/Prevention (PR&P)

IV. Infrastructure ..................................................................................................................................14

V. Recommended Investment Strategy .................................................................................................15

VI. Conclusion ......................................................................................................................................18

Appendix A: Evolving Nanotechnology Success Stories Pertinent to CBRE ........................................191. Nanoparticles for Chemical and Biological Agent Decontamination2. Nanoparticles for Sensitive, Selective Detection of CBRE agents3. Microcantilevers: An Ideal Sensor Platform for Terrorist Threat Detection4. Application of Nanomaterials to High Rate Mitigation of Chemical/Biological Threats5. Nanostructured Films for Chemical Sensing6. Rapid Development of Proteins for the Detection of Weapons of Mass Destruction7. Non-Invasive Monitoring of Cells for the Diagnosis of Pathogen Exposure and Infection

Appendix B: Acronyms.........................................................................................................................27

Appendix C: List of Participants and Contributors ................................................................................28

Nanotechnology Innovation for CBRE: Detection and Protection

Examples of nanotechnology applied to detection of and protection from chemical,biological, radiological, and explosive agents, from Appendix A of this report.

Executive Summary

Solutions to the problems of homeland security will be very complex and expensive to implement. Whyshould nanoscience/nanotechnology deserve an allocation from the limited resources that will be available?Nanostructures, with their small size, light weight, and high surface-to-volume ratio, will improve by ordersof magnitude our capability to:a) detect chemical, biological, radiological, and explosive (CBRE) agents with sensitivity (potentially as

little as a single agent entity) and selectivity (microfabricated sensor suites and molecular recognition)b) protect through filtration, adsorption, destructive adsorption or neutralization of agents (nanoporosity,

high surface-to-volume nanomaterials, and reactive surface sites)c) provide site-specific in-vivo prophylaxis.

The use of nanoscale sensors for CBRE can critically impact national security programs, by providingsensitive, selective, and inexpensive sensors that can be deployed for advance security to transportationsystems (protection for air, bus, train/subway, etc.); military (protection for facilities, equipment andpersonnel); Federal buildings (White House, U.S. embassies, and all other Federal buildings); customs (forborder crossings, international travel, etc.); civilian businesses; and schools. Nanotechnology-basedmaterials will be essential to protective garb for emergency response teams and hospital staff coping withchemical or biological (CB) incidents. New nanotechnology approaches to acceptable decontamination ofapparatus and building spaces are also needed, as highlighted by the prolonged efforts to decontaminateanthrax in the Senate Hart Office Building. The FY 03 NNI budget proposal identifies CBRE detection andprotection as one of 9 NNI “grand challenges” – targets for long-term benefits to the nation that could beexpected from the NNI’s basic research programs. The goal of this workshop was to recommend a plan ofaction for research and development under the auspices of the NNI aimed at realizing the promise of theCBRE grand challenge.

The workshop participants were polled to establish recommendations for needed science and technology(S&T) funding on the basis of three criteria:1) the importance of technology in coping with problems posed by CBRE protection/detection2) the potential for nanotechnology to contribute significant improvements to that technology3) the availability of resources/expertise ready to utilize effectively any funding allocation.An S&T goal of $100 million/year by FY05 was identified with a distribution of 50% in sensing, 30% inprotection and 20% in remediation.

Fundamental research will continue to be crucial to the full exploitation of nanotechnology. However, therealization of the short- and mid-term goals identified at the workshop will require availability of growingamounts of both applied research and Small Business Innovative Research (SBIR) funds. Approximatelyone half of the FY05 $100 million should be devoted to the explicit task of developing the technologyoptions. To accelerate the transition of nanoscience discovery into technology, the government agenciesaddressing new technologies for homeland defense — the DOD Joint Service Chemical and BiologicalDefense Program, the Defense Threat Reduction Agency, the Interagency Technical Support WorkingGroup, the DOE Radiological and Environmental Protection Program, and the DOT Weapons andExplosives Detection Program — should be knowledgeable of and actively participate in the nanotechnologyprograms.

The goal of $100 million by FY05 would consume about 10-15% of the anticipated U.S. NNI funding. Thatis a significant fraction of the NNI investment and, if met, might be detrimental to the rate of progress towardother NNI grand challenge goals. The CBRE terrorist threat is not unique to the United States. It is stronglyrecommended that joint programs be developed to incorporate the excellent and extensive European andPacific theater nanoscience into this CBRE detection/protection grand challenge program.

Chemical, Biological, Radiological, and Explosive (CBRE): Detection andProtection

I. Vision

Nanostructures, with their small size, lightweight, and high surface-to-volume ratio, will improve by ordersof magnitude our capability: a) to detect CBRE agents with sensitivity (potentially a single agent entity) andselectivity (microfabricated sensor suites, molecular recognition); b) to protect through filtration, adsorption,destructive adsorption or neutralization of agent (nanoporosity and high surface-to-volume nanomaterials);and c) to provide site-specific prophylaxis.

II. Relevance of Nanotechnology to CBRE

Explosives were introduced into warfare about 1100 AD1 and now dominate military weaponry. The use ofexplosives by terrorists is also common, with the 1993 bombing of the World Trade Center in New YorkCity, the 1995 bombing of the Alfred P. Murrah Federal Building in Oklahoma City, the 2000 bombing ofthe USS Cole in Yemen, and numerous 2002 suicide bombings in Israel as dramatic recent examples. Inaddition to political and symbolic targets, there is considerable threat to drinking water, wastewater treatmentplants, public transportation systems, and other important parts of our infrastructure such as chemicalmanufacturing plants and food processing industries.

While not as prevalent as explosives, the use of chemical/biological agents as a warfare or terrorist weaponreoccurs throughout history2. Scythian archers dipped arrowheads in manure and rotting corpses to increaselethality millennia ago. Tartars hurled dead bodies with plague over the walls of fortified cities in thefourteenth century. Smallpox-infested blankets were given to unfriendly native Indian tribes by the Britishduring the French and Indian war. WWI saw extensive use of chemical warfare. The Japanese introducedplague into Chinese cities in WWII. The Rajneeshee’s cult attacked cities in Washington State withsalmonella in 1984. The Aum Shinri Kyo deployed both anthrax and sarin gas in Tokyo in the early 1990s.Nature, more so than man, has proven to be a spectacular “terrorist” – smallpox, black plague, influenza, andHIV – have taken millions of lives. Diamond3 estimates that 95% of New World Indians may have died fromEuropean introduced (mostly unintentional) diseases.

Thus far no terrorist release of radioactive materials has occurred; however, accidental exposures in thenuclear power industry validate the potential problem, Chernobyl, Ukraine in 1986 being the most dramaticexample. Nuclear power plants, with their concentration of radioactive fuel and waste materials, areconsidered a potential target for terrorist action4. This, in addition to the possibility of nuclear devices on theblack market, establishes the threat and need for enhanced radiological screening, sensing, and clean-up.

1 A History of Warfare, J. Keegan (Alfred A. Knopf, New York, 1997).2 Germs, J. Miller, S. Engelberg, and W. Broad (Simon and Schuster, New York, 2001).3 Guns, Germs and Steel: the Fates of Human Societies, J. Diamond (W.W. Norton and Company, New York, 1999) pg211.4 “Chemical, Biological, Radiological and Nuclear (CBRN) Terrorism,” Report #2000/02, Canadian SecurityIntelligence Service.

One may expect nanotechnology to make significant contributions to the detection, protection, remediationand prophylaxis of CBRE events. Indeed, the DOE Basic Energy Sciences workshop report on “BasicResearch Needs to Counter Terrorism” cites nanoscience as one of the research directions to be emphasized5.Selected examples of evolving nanotechnology pertinent to CBRE detection and protection are provided inAppendix A.

IIA. Detection

Small amounts of chemical, biological, or radiological agents (see Table 1) can potentially inflict muchlarger scale damage to people than can equivalent amounts of explosive.

Table 1Comparative Lethality of Selected Toxins, ChemicalAgents, Biological Agents and Radiological Hazards

Agent Lethal Dosage (LD50 — •g/kg body weight) SourceBotulinum Toxin 0.001 BacteriumDiphtheria Toxin 0.10 BacteriumRicin 3.0 Castor BeanVX 15.0 Chem AgentGB 100.0 Chem AgentAnthrax 0.004-0.02* BacteriumPlutonium 1 Nuclear Fuel

*Anthrax calculations based on a spore volume of 5.0E-10 •l, an assumed spore density of 1.0 g/ml, and the LD50(lethal dosage to 50% of the population) estimated from the Sverdlovsk Model of 8,000 to 45,000 spores. Sincetheoretically one organism is capable of causing infection under the right conditions, body weight of the subject is notnecessarily relevant. Thus, the value for anthrax is not a true LD50, but could be considered as the weight of spores thatwould kill 50% of individuals in a statistically normal distribution.

Micrograms of anthrax and milligrams of nerve agent are sufficient to kill a person, as compared to grams ofhigh explosive. However, while larger amounts of explosive are necessary for deleterious consequences,their detection in the air is made difficult by low vapor pressures (particularly true for military explosives).As a practical consequence, it is necessary to find technology that will detect very small amounts of allCBRE material. As an illustration, the DOD detection requirements for chemical agents are listed in Table 2.

What role might nanotechnology play in the drive toward better detection against CBRE threats? Thenanoscale offers the potential for orders of magnitude improvements in sensitivity, selectivity, response time,and affordability.

SensitivityFor the nanoscience instrumentation being developed to measure and manipulate individual atoms with sub-nanometer precision, one pathogen or even one chemical molecule is huge. The detection of a single CBREentity comes within the realm of possibility.6 However there is still the nontrivial problem of getting thatsingle entity to the location where it can be detected.

5 “Basic research needs to counter terrorism,” Workshop Report, Office of Basic Energy Sciences, U.S. Department ofEnergy. http://www.sc.doe.gov/production/bes/counterterrorism.html (Feb. 2002).6 G.U. Lee, D.A. Kidwell, and R.J. Colton, “Sensing molecular recognition events with atomic force microscopy,”Langmuir 10, 354-7 (1994).

Table 2Joint Chemical Agent Detector Requirements

Agent* ThresholdConcentrationJCAD (mg/m3)

ThresholdResponse Time

Max (sec)

RelativeHumidity(%RH)

Temperature(C0)

10.10.04

0.001*

<10<30<90

5 to 100 -10 to +49

GA, GB, GD&GF

0.001**

<10<30

<18005 to 100 -30 to +49

HD, L&

<10<120<1800

5 to 100 -30 to +49 (HD &L)-15 to +29 (HN3)

AC2500

22<10<60 5 to 100 -32 to +49

CK 20 <60 5 to 100 -32 to +49

* See Appendix B for glossary of acronyms and other specialized terminology used in this report.** Maximum alert response time at low concentration (may use preconcentrator unit)

Diagnostic speed is a real issue for chemical, biological, and radiological exposures. For instance, secondsmay be all the time one has to respond to threat level quantities of nerve agent. Even with the slowerincapacitation rates for biological and radiological agents, detection times of seconds to minutes could limitthe exposure and simplify subsequent prophylactic action. If one can solve the problem of rapidly bringingsufficient quantity of agent into the detection volume, then nanostructures do minimize the time to diffuseinto and out of that volume. The nanoscale should also enable inexpensive sensor suites so that one canafford to distribute them prolifically and minimize the distance from a threat to a sensor.

SelectivitySelectivity is no less important than sensitivity. A detection system with frequent false positives (falsealarms) is quickly ignored (more likely discarded), while false negatives may lead to death. If presented witha small sample of unknown material for identification, the analytical chemist would turn to multiple, roomsized, sophisticated analytical tools – nuclear magnetic resonance, infra-red/raman spectroscopy, massspectrometry, elemental analysis – to ensure the identification. Reducing the size of a diagnostic toolgenerally leads to loss of performance. However, the nanoscale does enable the potential for sensor suites,where multiplicity in the tens to thousands may compensate for the loss of performance in any singlemeasurement. Further, nanoscience analytical tools make possible the measurement of additional molecularproperties – such as size, shape, and mechanics – not accessible by conventional analytical chemistry tools7.

Sample Collection/PreconcentrationThe collection of airborne or surface-attached samples representing a potential chemical, biological,radiological, or explosive threat is a key part of a point detection system. Nanostructures can be sufficientlysmall and light to avoid gravitational settling. There is the possibility for maneuverable nanostructures thatwould circulate through large volumes of air or water and then be proactively drawn (throughmagnetic/electric field coupling) to the sensor. A front-end collection system must match the flow

7 “Direct measurements of the interaction of single strands of DNA with the atomic force microscope,” G.U. Lee, L.Chrisey, and R.J. Colton, Science 266, 771-3 (1994); “A biosensor based on force microscope technology,” D.R. Baselt,G.U. Lee, and R.J. Colton, J. Vac. Sci. Technol. B14, 789-93 (1996).

impedance of the nano-detection sensor for the system to be fully functional. The most efficient collectionsystems would employ some type of preconcentration media, which requires research and development ofnanoscale coatings (e.g., development of monolayer polymer coatings for chemically selective, rapidabsorption/desorption of agent molecules).

In-vivo SensingNanotechnology will accelerate the development of sensing systems capable of in-vivo operation. One canenvision sensors that sample body or cellular chemistry to detect the very early stages of exposure tochemical, biological, or radiological agents.

Radiological SensingThe nanoscale offers a mixed opportunity for the detection of radiation. As with the detection ofchemical/biological threats, the properties of a nanostructure will be significantly affected by the capture of ahigh-energy particle. However, in contrast the chemical/biological threat, nanoscale dimensions will makethat capture difficult; the mean free path is longer than a nanometer for detection of the distinguishingneutrons and gammas of relevant isotopes. Detection in nanoscale ranges might be possible for thermalneutrons and airborne radioisotopes using solid-state detection techniques. There has already been asignificant amount of work to reduce the volume of radiation detectors. That miniaturization, coupled withthe miniaturized chemical and biological detection devices, will enable the incorporation of chemical,biological, and radiological (CBR) detection into a single package.

Remote DetectionRemote sensing can be accomplished either by unattended sensor suites or by stand-off detection. Theformer are essentially the point detectors discussed above, but with special emphasis on achieving obscurity(small, passive) and low power. Communication with the suite would need be rapid (for power andcovertness reasons); the incorporation of nanoelectronics for local intelligence will enable transmission ofcompact information, not voluminous raw data.

Stand-off detectors may offer a more flexible approach to sensing, and require active and/or passivedetection of photons. One-dimensional nanotechnology is already providing variable frequency lasers inspectral ranges that might provide molecular fingerprints8. These new sources, coupled with one-dimensional approaches to sensitive, narrow band detection of photons, may lead to miniaturization ofspectrometers. The use of nanostructures in photonic band gap devices should lead to further innovations.

Potential ApplicationsThe use of nanoscale sensors for CBRE can critically impact national security programs and emergencyresponse team safety by providing sensitive, selective, and inexpensive sensors that can be deployed foradvance security to transportation systems (security protection for air, bus, train/subway, etc.); military (forprotection of facilities and equipment); Federal buildings (White House, U.S. Embassies, and all otherFederal buildings); customs (for border crossings, international travel, etc.); civilian businesses; and schools.The potential impact is vast and critical.

IIB. Protection

Gas mask filters used in nuclear, biological, and chemical (NBC) applications remove toxic chemicals by aprocess that is essentially WWI technology. The material responsible for chemical vapor/gas removal is anactivated carbon with metal oxides (such as, copper, zinc, molybdenum, and silver) impregnated in the largercarbon pores using a Whetlerite method. For additional protection against blood gases, triethylenediamine(TEDA) is added. The NBC filters rely on high surface areas for efficient adsorption of low vapor pressurechemical warfare agents or toxic industrial compounds. Higher vapor pressure chemicals, not removed

8 “Quantum cascade lasers,” F. Capasso, C. Gmachl, D.L. Sivco and A.Y. Cho, Physics Today 55(5), 34-40 (2002).

efficiently by adsorption, are retained by chemical reaction with the carbon's impregnates. Generalrequirements for protective masks and clothing are itemized in Tables 3 and 4.

Table 3CBW Protection Requirements for Filter Masks 9

Aerosol Filtration 99.990 % (smoke concentration of 100 •g/L, flow rate of 32 L/min;avg particle diameter 0.3 •m)

Canister Use Life (Gas Exposure)Sarin 83 min (to break point of 0.04 mg/m3 at concentration 4,000 mg/m3)CK 30 min (to break point of 0.04 mg/m3 at concentration 4,000 mg/m3)DMMP 59 min (to break point of 0.04 mg/m3 at concentration 3,000 mg/m3)

Table 4Chemical Protective Clothing Performance Requirements10

Garment Type Challenge Type Challenge LevelVaporHD,TGD,VX

5,000 ct(mg-min/m3)

MOPP ProtectiveOvergarment

LiquidHD,TGD,VX

5-10 g/m2

VaporHD, TGD, VX

5,000 ct(mg-min/m3)

MOPP ProtectiveUndergarment

Liquid 10 g/m2

VaporCBs,TICs, POLs, Rocket Fuels

5,000 ctSTEPO (self-contained toxicenvironment protective outfit)

LiquidCBs,TICs, POLs, Rocket Fuels

10 g/m2

VaporHD,VX,GB,L

5,000 ct(mg-min/m3)

ITAP (improved toxicological agentprotective ensemble)

LiquidHD,VX,GB,L

10 g/m2

AdsorbentsActivated carbon is replete with pores with dimensions ranging from about 0.5 nm to 500 nm; it is anempirically derived nanotechnology. Nanoscience can provide new opportunities for high surface areaadsorbents and molecular templating that augments the bonding strength. Many toxic industrial chemicalsand acid gases (CS2, HCN, SO2, H2SO4, etc.) are not well adsorbed by charcoal or activated carbon.Nanoparticle oxides offer a possible answer here, because they can be tailored to have solid acid or solid baseproperties; the adsorptive properties can be tailored from the “ground up.” Nanostructures also offer thepossibility for selective adsorption of radioactive materials (not due to the radioactivity, but to other knownchemical properties of these materials).

Filtration/SeparationCollective protection systems and protective clothing generally utilize fibrous filters to remove agents. Highefficiency particulate air (HEPA) filters can be effective against particulates; even the biological toxins thatmight be dispersed as aerosols could be filtered out by HEPA. The use of nanotubes, nanofilaments, andnanoporous membranes might make these filters even more effective, and might incorporate catalytic 9 Military Performance Standard MIL PRF 51560A (EA)10 Joint operational requirement document (JORD) for a lightweight integrated nuclear, biological, and chemical (NBC)protective garment (No. NBC 215.1,1995)

degraders as well. For example, it has been shown that membranes containing nanotubes with diameters ofmolecular dimensions can be used to filter small molecules on the basis of size, and that chemical andbiochemical reagents can be incorporated to make highly selective molecular recognition membranes11.Nanoporous membranes have been shown capable of removing virus particles from water12; NASA has anSBIR project to evaluate a ceramic nanofiber filter to remove viruses from drinking water on theInternational Space Station13. Smart membranes are also under development that respond to particularchemical or biological agents and switch on in response to their presence14. Nanosized molecules can betailored for the sequestration of radionucleotides15. Catalytic and photocatalytic agents added to HEPA filtersoffer the real possibility to make these structures self-cleaning and self-sterilizing thereby greatly extendingsystem life while reducing life-cycle costs. Reductions in power and operational costs may also be providedby electrically conductive filter media, which feature reduced pressure drop (larger pore size) yet highercapture efficiency when used as part of a catalytically or photocatalytically regenerable HEPA collectionelectrode in a electrostatic precipitator.

Decontamination and Neutralization of Dispersed AgentsDecontamination and neutralization of harmful moieties can also benefit from nanoscale materials. Toensure their general effectiveness and to simplify logistics, the military decontamination solutions havetraditionally been highly aggressive chemicals. The Navy decontamination (decon) solution (ASH/SLASH)utilizes hypochlorous acid; the Army decon solution (DS2) utilizes sodium hydroxide and diethlenetriamine.Unfortunately, while effective against agents, these chemicals also attack incidental materials, includinghuman skin.

Catalytic nanostructures, both inorganic and organic, should improve this situation as nanoscience providesclearer understanding of composition/structure versus function relationships. Nanoparticles such asnanotubes that incorporate biochemical catalysts will lead to an arsenal of smart nanoparticles for specificremediation applications. The key point here is that such smart nanoparticles will allow for reduced use ofhighly aggressive chemical systems. Nanophase photocatalytic materials incorporated into paints, pigments,and other coatings offer the opportunity to provide self-cleaning and self-sterilizing surfaces16; they wouldoperate in a passive or active mode with significantly less risk and side effects than current decontaminationprocedures and chemicals. Nanoemulsions have been shown to be very effective against a number ofbiological infective agents such as anthrax17. Further, as the role of nanostructures in cellular activity isbetter understood, new mechanisms to disrupt and neutralize harmful pathogens are being discovered18.

11 “Antibody-based bio-nanotube membranes for enantiomeric drug separations,” S.B. Lee, D.T. Mitchell, L. Trofin,T.K. Nevanen , H. Soderlund, and C.R. Martin, Science 296(5576) 2198-2200 (2002).12 “French drink tap water? Oui, if it’s nanofiltered,” Genevieve Oger, Smalltimes News articlewww.smalltimes.com/document_display.cfm?document_id=39413 “Filters based on novel bioactive nano fibers,” F. Tepper and L. Kaledin, Argonide Corporation,www.argonide.com/bioactive.htm14 “Ion channel mimetic micropore and nanotube membrane sensors,” E.D. Steinle, D.T. Mitchell, M. Wirtz, S.B. Lee,V.Y. Young, and C.R. Martin, Analytical Chemistry 74(10), 2416-22 (2002).15 “Selective metals determination with a photoreversible sprobenzopyran,” G.E. Collins, R.E. Shaffer, V. Michelet, andJ.D. Winkler, Analytical Chemistry 71, 5322 (1999); “Microfabricated capillary electrophoresis sensor for uranium(VI),” G.E. Collins and Q. Lu, Analytica Chimica Acta 436(2), 181-189 (2001).16 “Application of titanium dioxide photocatalysis to create self-cleaning building materials,” R. Benedix, F. Dehn, J.Quaas and M. Orgass, Leipzig Annual Civil Engineering Report (5), 157 (2000). Institut for Massivbau undBaustofftechnologie, Wirtshaftswissenshhaftliche Fakutat, Leipzig, FRG.17 “A novel surfactant nanoemulsion with a unique non-irritant topical antimicrobial activity against bacteria, envelopedviruses and fungi,” T. Hamouda, A. Myc, R. Donovan, A.Y. Shih, J.D. Reuter, and J.R. Baker, MicrobiologicalResearch 156(1), 1-7 (2001).18 “Antibacterial agents based on the cyclic D,L-alpha-peptide architecture,” S. Fernandez-Lopez, H.S. Kim, E.C. Choi,M. Delgado, J.R. Granja, A. Khasanov, K. Kraehenbuehl, G. Long, D.A. Weinberger, K.M. Wilcoxen, and M.R.Ghadiri, Nature 412(6845), 452-5 (2001).

Large-Scale CBRE Mitigation and Chemical ProcessingThe destruction of old, existing U.S. chemical agents illustrates a different aspect of “neutralization.” Thedestruction of quantities of agents poses major problems – the extreme toxicity of chemical/biological agentsrequires highly effective destruction. The incorporation of nanomaterials into chemically reactive structurescan take advantage of the intrinsic nanostructure surface kinetics and selectivity, while providing appropriatemicro- and mesostructure to accommodate the required transport process, thermal management, low pressuredrop, etc.

Green ManufacturingNanotechnologies hold the promise of less toxic chemical processing. Hence, hazardous materials andwastes may be eliminated or minimized and their potential for use in terrorist attacks reduced. For examplenanocrystalline metal oxides have been shown to enable the following chemistries: (1) catalytic solventlessdehydrochlorination of chloroalkanes, (2) catalytic selective alkylation reactions using superbasenanomaterials, (3) catalytic alkane isomerization reactions using super acid nanomaterials, and others.

Potential ApplicationsPerhaps even more important than adequate sensing, protective clothing will be essential to emergencyresponse teams and hospital staff coping with CB incidents. New nanotechnological approaches toacceptable decontamination of apparatus and building spaces are needed, as highlighted by the prolongedefforts to decontaminate the anthrax in the Hart Senate Office Building.

III. Nanoscience/Nanotechnology Research Opportunities

IIIA. Transition Opportunities

The U.S. National Nanotechnology Initiative (NNI) has its prime focus on science. It traditionally takes 10-20 years for scientific discovery to evolve into fielded technology. However, the NNI builds on two decadesof Federal funding at the nanoscale. There is a range of opportunities for commercial products, some withnear-term reach (1-5 year), others likely in the mid-term (5-10 years), and yet others where complexity orlack of present understanding will require long-term science investment (10-20 years).

Table 5Potential Near-Term Nanotechnology with CBRE Impact

Investigator Institute Technology CompanyBaker Michigan nanostructured bio decon NanoBio Corp.Doshi - polymer nanofibers eSpinHellinga Duke U. Tailored biosensors Johnson & JohnsonKlabunde Kansas State nanocluster agent

catalysisNanoscale Materials

Lieber Harvard nanotube sensors NanosysMartin U. Florida nanotube membranes Broadley-James Co.Mirkin Northwestern nanoAu biological

sensingNanosphere

Russell Univ Pittsburgh sensing wipe AgentaseSmalley Rice CNT for adsorbents CNISnow NRL nanoAu chemical

sensingMicroSensor Systems

Tatarchuk Auburn CNT adsorbent media IntraMicron IncThundat ORNL cantilever sensing ProtiverisWalt Tufts U. nanoarray sensors Illumina

Short-Term (1-5 yr) Transition OpportunitiesFor transition into commercial product inside of five years, these opportunities must already have: a)demonstrated proof-of-principle and b) existing commercial involvement. Specific examples are itemized inTable 5.

Funding to accelerate these opportunities might come from the mission-oriented agencies such as DODwhere 6.2-6.4 monies are available for the development of new technology; the DOT Transportation SecurityAdministration; and the Office of Homeland Security. The NSET member agencies must also continue toexploit the SBIR/STTR programs to accelerate commercial transitions.

Mid-term (5-10 yr) Transition OpportunitiesAreas where an investment in nanoscience holds the promise for paradigm breaking approaches todetection/protection with commercial product transition in the 5-10 year time frame are as follows:

• SensingTransduction/actuation mechanisms for greater sensitivity/selectivityBiotic/abiotic interfaces to marry semiconductors with in-vivo biologyEnvironmental energy sources to minimize battery requirementsIncorporate separation and detection technologies at micron scales with lab-on-a-chip

• ProtectionHigh surface area materials with templated structure for selective adsorptionControlled porosity for selective migration and separationNanofibers and nanotubes for clothing with improved adsorption/neutralization of agentsSmart materials for control of diffusion and active mass transportSmart nanoparticles that recognize and sequester or destroy specific toxinsLarge scale structured packings, coatings, and other media with optimized microstructure to

enhance/accommodate key underlying transport issues• Neutralization/Decontamination

Nanostructures to disrupt biological functionCatalytic nanostructures

• PreventionNanostructures to reduce or replace hazardous substances in manufacturingNanostructures that selectively bind and decompose hazardous substances

• TherapeuticsEncapsulated drugs for targeted releaseCombination of therapeutics with imaging agents for monitoringIntracellular drug deliveryTargeting radio and optical energy to localized sitesBioscavengers

Nanoparticle for detoxification, e.g., chemical agents in blood

Long-term (10-20 yr) Transition OpportunitiesAreas where an investment in nanoscience is important for integrating many components into a complexsystem (e.g., sensor suites) or for providing sufficient insights into a complex system (e.g., cell physiology)to enable innovative nanotechnologies include the following:

• Multifunctional surfacesDevelop surfaces that contain sensing and reactive moieties for protection, self-decontamination, and

self-sterilization

• Cell-based sensingDevelop sensing technology that responds to unknown new threats by measuring the response of

living systems that mimic human biochemistry• In-vivo diagnostics

Sophisticated, body powered, in-vivo diagnostics for identifying physiological abnormality• NEMS

Extend microelectromechanical systems (MEMS) technologies another three orders of magnitudesmaller in order to incorporate significantly greater capability

• Laboratory on a chipIncorporate multiple separation and detection technologies at sub-micron scales on a single chip in

order to get inexpensive rapid detection technology for all threat agents (chemical,biological, explosive and radiological) and to minimize false positive/negative events

• Hierarchical self-assemblyMake innovative approaches to directed self-assembly in multiple dimensions viable, otherwise

incorporation of greater complexity into detection/protection systems will be overlyexpensive

IIIB. Nanoscience Opportunities for Detection: Miniaturized, Intelligent Sensors (MIS)

VisionTo develop nanoscience and nanostructures that more effectively collect and deliver samples to sensitive,selective sensors (chemical, biological, radiological, electromagnetic, acoustic, magnetic, etc.) withinformation processing electronics and communication for miniaturized, intelligent sensor suites that canactively respond to homeland defense requirements.

MIS Homeland Defense ImpactMiniaturized, intelligent sensors that will enable important new capabilities to counter CBRE threats tocivilian and military populations include the following:• Lighter, smaller, and highly functional systems to provide rapid detection of threats, and communication

systems with greater versatility and bandwidth will affect the performance and safety of the participantsin prevention/remediation of CBRE incidents.

• With sensing/detection/signal processing at nanometer scales, surveillance “platforms” can beinconspicuous and sufficiently inexpensive to enable prolific coverage of enclosed spaces such as officebuildings and transportation hubs.

• Uninhabited vehicles for reconnaissance could reduce the risk to human lives.• Personal monitors for CBRE threats, physiological fatigue, and medical applications require the linkage

of biological functions with nanostructured semiconductor devices. Small sizes will be required for afunctional system to be embedded in the body where it can detect the small changes in body chemistryincipient to more severe problems, and can initiate corrective action. Small size will also facilitate theincorporation of molecular phenomena (synergistic with biotic systems) into electronic devices(presently abiotic).

MIS ProgramTo best exploit the opportunities, MIS requires an interdisciplinary approach to the development ofsensing/information processing, decision, and actuation. The MIS program should address the followingissues:

1. Sample collection and concentration2. Sensing, actuation, and transduction

Transduction properties of individual nanostructures, polymers and proteinsTransduction properties of nanostructure arrays

Molecular machine/nanomachine conceptsTethered nanodots/nanowires with magnetic/electric field actuationMagnetic/electric/optical/chemical signalingArtificial cells

3. Molecule – semiconductor/metal interfaceThe balance of bond stress and bond energy in surface reconstructionElectron/hole transfer between molecule/biomolecule and semiconductorNovel bonding chemistry

4. Biotic and abiotic interfacesSurface compatibility of semiconductors in aqueous/physiological environmentLinkers with retention of biological function such as molecular recognitionMembrane gatingDevelopment of functional interconnects between nanoscale building blocks

5. Fabrication with a focus on assembly of building blocks (i.e., nanodots, nanowires, etc.)Techniques for patterning and fabrication of circuits with nanostructuresHierarchical assembly of functional arraysDirected assembly utilizing designated chemical/molecular recognition eventsNanodevices: shape, size, defects, and impurities

6. Methods to model and design nanostructure properties and nanodevice performance7. Power sources

New methods, materials and devices to harvest energy from the environmentAbility to interconnect power sources with nanostructures and complex architecturesMolecular motors

IIIC. Nanoscience Opportunities for Protection/Remediation/Prevention (PR&P)

VisionTo develop nanoscience and nanostructures which enable revolutionary advances in adsorbent materials(personal and collective protection), separation technologies (protective clothing and filters),neutralization/decontamination of agents, and prophylactic measures.

Homeland Defense ImpactEmpirically derived nanoscaled materials have been a mainstay in CBRE protection and neutralization.Attention to the underlying nanoscience base should lead to dramatic improvements, especially as thatknowledge enables the development of more sophisticated systems, such as:• Decontamination via aggressive chemical systems, damaging to human and equipment as well as CB

agents, can be replaced by treatments as effective at decontamination but benign to humans and theenvironment.

• Specific smart nanoparticle decontaminating agents.• Decontamination of sensitive equipment (water not allowed).• Protective clothing and personal protection filters that incorporate decontamination activity rather than

simple adsorption, and permit water vapor migration for cooling.• Masks/filters with adsorbents having greater selectivity and capacity for harmful agents, incorporating

miniaturized sensing to detect breakthroughs, and potentially neutralize the agents.• Innovative approaches to the deactivation of biological agents, especially spores.• Manufacturing and processing industries free of hazardous materials and wastes.• Artificial nanosystems for on-site and on-demand chemical and biological synthesis.• Novel carrier technologies and strategies that allow emerging bulk phase nanomaterials to be placed into

large-scale structured packings, monoliths, coatings, electrodes, and other media while optimizingoverall system microstructure so as to enhance or accommodate key underlying transport issues (i.e.,

heat, mass, ions, electrons, etc.) and to capitalize on the benefits provided by desirable nanomaterialsurface kinetics and selectivity.

Protection/Remediation/Prevention ProgramTo best exploit the opportunities, PR&P requires an interdisciplinary approach to the development ofnanostructures that selectively interact with CBRE molecules. A PR&P program should address thefollowing issues:

1. High-surface area, selective adsorbentsNon-carbon adsorbentsTemplated surfaces for more selective adsorptionNanotubes and nanotube membranesHierarchical control of porosity for low-pressure dropIncorporation of catalytic decomposition for agent destructionBiomolecular adsorbent/filtration materials

2. Catalytic materialsProteins as biological enzymesTailored nanoclusters for selective catalysis and benign productsTunable photocatalystsEnvironmentally benign catalysts

3. Nanostructures for clothing/separatorsFabrication of polymer nanofilamentsIncorporation of catalytic centers in fibersFiber surface modificationNanoporous materialsDesigned nanostructured membranes

4. Nanostructures capable of disrupting biological agent functionNanoemulsionsProtein and synthetic nanotubes for membrane disruption

5. Prophylactic nanostructuresMEMS/NEMS for drug deliveryNanotherapeutic delivery platformsIntracellular monitors for infection/radiation damageNanostructured reactors in skin creamsNanostructured materials for wound cleansing and treatment

6. Low cost, high-speed manufacturing techniques that incorporate desirable bulk phase nanomaterialsinto fabrics, papers, composites, covers, packaging materials, and porous media suitable for chemicalprocessing and mitigation applications at both the smallest and largest application levels.

IV. Infrastructure

MEMS/NEMS fabrication facilities will be necessary to implement the sensing goals. Nano-powder andnano-filament production scale-up will be necessary to implement the protection goals. New materialshandling technologies and modifications to existing processes will be needed to incorporate bulk phasenanomaterials into existing manufacturing and distribution infrastructure. It is expected that theserequirements will be met by other parts of the NNI program.

Since any new technology must ultimately be tested against real agent, access to surety test and evaluationfacilities in the Joint Chemical and Biological Defense Program must be included in this grand challenge.This testing is expensive; adequate funding must be available.

V. Recommended Investment Strategy

The workshop participants were polled for their opinions on S&T funding distribution on the basis of threecriteria:

1) the importance of technology in coping with the problems posed by CBRE protection/detection2) the potential for nanotechnology to contribute significant improvements to that technology3) the availability of resources and expertise ready to utilize effectively any funding increase.

1. Funding Distribution

After the group decided on the appropriate topics/subtopics to be funded, each participant independentlydesignated a percentage for each subtopic. The averaged distribution is reported in Table 6. The result has adistribution of approximately 50% in sensing, 30% in protection and 20% in remediation.

Table 6Federal Nanotechnology S&T Balance Recommended by Workshop Participants

Topic Subtopic Avg(%)

StandardDeviation

SensingBiological 13 6Chemical 10 4Radiological 6 3Explosive 10 5Sample Collection 4 3Remote 3 3

ProtectionAdsorption 11 5Separation 8 4Neutralization 13 4

Site RemediationBiological 8 5Chemical 8 3Radiological 6 3

While therapeutics is clearly an important topic for CBRE S&T, the workshop participants believe theadvanced healthcare grand challenge would adequately cover this topic. Similarly, it was decided that threatreduction by reducing the amounts of hazardous materials utilized in manufacturing, while valuable, shouldbe part of the manufacturing at the nanoscale and environmental grand challenges.

Table 7 shows the distribution of the FY01 investment by the NNI agencies in topics directly relevant tonanotechnology for CBRE Protection/detection. The FY01 funding was used since FY02 funding was stillevolving at the time of this workshop. A goal of $100 million total investment by FY05 was identified asworthwhile.

Outside of the present investment in nanotechnology for chemical and biological sensing, there are clearprogram deficiencies. Further, while the discovery aspect of fundamental research is clearly crucial, therealization of the short- and mid-term goals for technology options will require availability of growingamounts of both applied research and SBIR funds. It is recommended that approximately one half of the$100 million should be devoted to the explicit task of developing those options (see Table 8).

Table 7Government S&T Investment ($ millions)

Topic Subtopic FY01(est)

FY05(recom)

SensingBiological 15 13Chemical 13 10Radiological 6Explosive 10Sample Collection 4Remote 3

ProtectionAdsorption 0.5 11Separation 0.5 8Neutralization 4 13

Site RemediationBiological 8Chemical 8Radiological 6

Total 33 100

Table 8Federal S&T Investment in Nanoscience CBRE by Funding Type ($ millions)

FY01 FY02 FY03 FY04 FY05Fundamental 31 26 35 45 55Applied 10 20 30 40SBIR/STTR/ATP 2 2.5 3 4 5Total 33 100

2. Leveraging Among Participating U.S. Government Agencies and International Efforts

The CBRE grand challenge should achieve critical mass in nanoscience toward its aggressive goals byleveraging the other NNI research programs (and other nanoscale R&D), especially the NASA programs inmicrosatellites; the DOE programs in environmental sensing; the NIH programs for medical sensors andtherapeutics; the NSF programs in simulation/modeling and green manufacturing; the EPA programs inimproved sensors, treatment/remediation, and hazardous substance reduction/elimination; the DOT programsin trace explosives detection; and the DOD programs in nanoelectronics, molecular electronics andchemical/biological defense.

The goal of $100 million by FY05 would require about 10% of the anticipated U.S. annual NNI funding.That is a significant fraction of the NNI investment and might be detrimental to the rate of progress towardother grand challenge goals. The CBRE terrorist threat is not unique to the United States. It is stronglyrecommended that joint international programs be developed to incorporate the excellent and extensiveEuropean and Pacific theater nanoscience on CBRE detection and protection.

3. Cross-disciplinary and University/Government Laboratory Linkages

It is critical to integrate the biology, chemistry, engineering, materials and physics research communities toestablish the interdisciplinary nanoscience knowledge and expertise needed to exploit nanostructures in thedevelopment of the following:

• Miniaturized, real-time, intelligent, redundant sensor systems with revolutionary CBRE detectionperformance

• New high-surface area templated adsorbents for personnel/collective protection and decontaminationsystems, potentially incorporating catalytic reactive systems

• Nanofiber/nanoporous membranes for effective protective clothing without undue heat loading,potentially incorporating catalytic materials to neutralize agents while remaining relatively benign tohumans and the environment

• Mechanisms to disrupt the viability of biological agents• Multifunctional materials that recognize and generate a response to a threat agent• Nanoscale processes that reduce or eliminate the use or production of hazardous substances

The grand challenge should strengthen the linkages between the university research communities and theDOD/DOE/NIST laboratories where CBRE test, evaluation and systems innovation have traditionally beenperformed.

4. Interagency Coordination

To maximize the rates of scientific discovery and its technology transition, this grand challenge must exploitthe traditional strengths of the NNI participating agencies/departments:DOD chemical/biological agent – sense/protect/mitigate/decon; landmine senseDOE radiological/explosive; system integration – lab-on-a-chipDOJ/NIJ chemical/biologic agent – sense/protect; DNA forensic analysisDOT explosive detection; advanced transportation security systemsEPA chemical/biological detection; decon/neutralization; hazardous substance reductionNASA system integration; miniaturization; robotic systemsNIH therapeutic treatment for chemical/biological/radiological exposureNIST chemical microsensors, single molecule measurementNSF fundamental science underpinningsState/Intel detection for treaty verification and non-proliferation

Coordination amongst many of these agencies at the technology level already happens through the TechnicalSupport Working Group (TSWG). The estimated FY 01 nanoscience investment levels are shown inTable 9.

Table 9FY01 Agency Investment in Nanoscience/Nanotechnology Relevant to

CBRE Protection/Detection ($ thousands)Topic Subtopic DOD DOE DOT EPA NASA NIH NIST NSF Totals

SensingBiological 7.5 7 14.9Chemical 6.6 5.5 12.5RadiologicalExplosiveSample CollectionRemote

ProtectionAdsorption 0.5 0.5Separation 0.4 0.4Neutralization 1 1.6 1.8 4.4

RemediationBiologicalChemicalRadiological

The grand challenge should couple closely with existing programs that address the CBRE threat, especiallythe DOD Joint Service Chemical and Biological Defense Program19, the Defense Threat Reduction Agency,the Interagency Technical Support Working Group (TSWG, http://www.bids.tswg.gov), the DOERadiological and Environmental Protection Program, and the DOT Weapons and Explosives DetectionProgram (aviation). The NNCO should approach these agencies to solicit further guidance for the bestinvestment strategy, and to engage agency interest/funding in the recommended applied research efforts.This involvement will ameliorate the “not-invented-here” syndrome that frequently stifles technologytransition.

VI. Conclusion

It is clear that nanotechnology has the potential to dramatically ameliorate the problems associated withterrorist use of chemical, biological, explosive and radiological threats. The development of a broad range ofnew, sensitive, selective, nanotechnology-based sensors for chemical, biological and explosive threats isimminent. Miniaturization enabled by the nanoscale offers opportunities for integrating sensor capabilitiesand detecting all four of the threat classes with a single, low power, handheld unit. The high surface-to-volume ratio for nanostructures will also lead to dramatic improvements in protection and remediation. Forexample, nanostructures are key components in cellular physiology, and nanoscience is already providingnew insights into the disruption of bacterial agent physiology. The recommend funding goal fornanotechnological approaches to CBRE is $100 million by FY05, distributed as 50% in sensing, 30% inprotection and 20% in remediation. The present investment is approximately $30 million and is mostlyfocused on sensing. There are nanotechnology opportunities for the short, mid and long range. In addition tofunding fundamental research, there should be growing funds for applied research with the goal of roughly a50/50 mix by FY05.

19 “Department of Defense, Chemical and Biological Defense Program, Annual Report to Congress,” March 2000;DTIC ATTN: DTIC-E (Electronic Document Project Officer), 8725 John J. Kingman Road, Suite 0944, Fort Belvoir,VA 22060-6218.

Appendix A: Evolving Nanotechnology Success Stories Pertinent to CBRE

A.1. Nanoparticles for Chemical and Biological Agent Decontamination

Decontamination and destruction of chemical and biological warfare agents in the field is of great importanceto the warfighter. New reactive adsorbents for the removal of toxic materials and chemical warfare agentsare a priority need for the Army. The Army Research Office has been supporting Professor KennethKlabunde at Kansas State University to study the fundamental chemistry of nanoparticles for several yearsnow. Nanoparticles are very small particles with increased surface area and reactivity. One-quarter ounce ofnanoparticles has the same surface area as a football field.

Figure A.1. Powdered sorbent being used to decontaminate a soldier.

Certain nanoscale particles are reactive in neutralizing both chemical and biological agents. Methods todisperse the nanoparticles via mitts (like the M-295 Immediate Decon Kit or Sorbent DecontaminationSystem, Figure A.1) or sprayers (like the M-11, Figure A.2) are underdevelopment. The nanoparticles arecurrently being evaluated by the U.S. Army Edgewood Chemical Biological Center, U.S. Army MedicalResearch Institute for Chemical Defense, Natick Solider Center, Dugway Desert Test Center, and theDefense Evaluation and Research Agency of the United Kingdom.

Figure A.2. Powdered sorbent being sprayed from a devicesimilar to the M-11 sprayer.

Nanocrystals of Al2O3 and Al2O3/MgO have been produced by an alkoxide based synthesis involving thecorresponding aluminum tri-tert-butoxide, magnesium methoxide, toluene, methanol, ethanol, and water.The resulting oxides are in the form of powders having crystallites of about 2 nm or less in dimension.These crystallites have been studied by transmission electron microscopy (TEM), and Brunauer-Emmet-Teller (BET) methods, and were found to possess high surface areas and pore volumes (800 m2/g for Al2O3,790 m2/g for Al2O3/MgO, compared to 450 m2/g for MgO). As seen with other metal oxides, once they aremade as nanoparticles their reactivity is greatly enhanced on a per unit surface area basis. This is thought tobe due to morphological differences, whereas larger crystallites have only a small percentage of reactive siteson the surface, smaller crystallites possess much higher surface concentration of such sites per unit surfacearea. Reactions with CCl4, SO2, and paraoxon have demonstrated significantly enhanced reactivity and/orcapacity compared with common commercial forms of the oxide powders. An important finding is that thecombination of Al2O3 and MgO allows for unexpectedly high surface areas and with a combination of Lewisacid and Lewis base character. The results show: a) intermingling has enhanced reactivity/capacity, over thepure forms of nanoscale Al2O3 or MgO, toward chemical warfare surrogates (paraoxon) and an acid gas(SO2); and b) tailored synthesis of a nanoparticle formulation can yield special benefits, and demonstratesjust one example in thousands of possibilities.

Table A.1Examples of Enhanced Capacities of Intimately Intermingled Nanoscale Moieties of Al2O3 and MgO

Sample Total molecules of SO2

adsorbed per nm2 ofnanoparticle oxide

mmoles paraoxon destructivelyadsorbed by one mole nanoparticle

MgO 6.0 22

Al2O3 3.5 91

Al2O3 /MgO 6.8 180

References(1) Corrie Carnes, Ph.D. Thesis, Kansas State University, 2000.(2) C. L. Carnes, P. N. Kapoor, K.J. Klabunde, and J. Bonevich, Chem. Materials 14(7), 2922-2929 (2002).

A.2. Nanoparticles for Sensitive, Selective Detection of CBRE agents

The analytical tools being developed for nanoscience must locate and measure the properties of single atoms.This precision can be adapted to sensing with exquisite sensitivity. Several sensor concepts are undercommercial development for chemical and biological agent detection. As an example of chemical sensing,organothiol stabilized nanosized Au clusters have been self-assembled between two microfabricatedelectrodes. The current flowing between the electrodes depends on electron tunneling through the organicfilms. Small amounts of chemical agents in the air surrounding the sensor can partition into the organic andcause changes in its dimension or dielectric constant (1). Both effects cause exponential changes in electricalcurrent; parts-per-billion of chemical agents have been detected by this approach. Utilizing patternrecognition techniques, an array of sensors – each with a different organic constituent – provides theselectivity. This technology is under commercial development by MicroSensor Systems Incorporated(Figure A.3). As an example of biological sensing, it has been shown that nanosized Au clusters in solutionhave different colors, depending on their separation. If appropriately chosen strands of DNA are attached tothe clusters, the presence of its complement can cause the clusters to be “glued” together and change color.A lower detection limit for this system has been demonstrated of 500 pM for a 24 base single-stranded targetand 2.5 nM for a duplex target nucleotide (2). It has been shown that anthrax DNA can be sensitivelydetected by this technique; commercial development is underway by Nanosphere Inc. (Figure A.4).

References(1) “Colloidal metal-insulator-metal ensemble chemiresistor sensor,” H. Wohltjen and A.W. Snow

Analytical Chemistry 70, 2856-2859 (1998); “Gold nanocluster vapor sensors,” A.W. Snow, H.Wohltjen, and N. L. Jarvis, Abst of Papers at the American Chemical Society 221: 324-IEC, Part 1 Apr 1,2001.

(2) “A gold nanoparticle/latex microsphere-based colorimetric oligonucleotide detection method,” R.A.Reynolds, C.A. Mirkin, and R.L. Letsinger, Pure and Applied Chemistry 72, 229-235 (2000);“Homogeneous, nanoparticle-based quantitative colorimetric detection of oligonucleotides,” R.A.Reynolds, C.A. Mirkin, and R.L. Letsinger, J. Am. Chem. Soc. 122 (15), 3795-3796 (2000).

Fig. A.3. MicroSensor Systems Inc.handheld chemical sensor basedon nanoparticle Au (1).

Fig. A.4. Color change in Au nanoparticleslocalized by DNA sequencerecognition (2).

A.3. Microcantilevers: An Ideal Sensor Platform for Terrorist Threat Detection

A widespread need exists for portable, real-time, low-power, in-situ sensors for detection of terrorist threatssuch as nuclear radiation, biological and chemical warfare agents (BCW), and explosives. Unfortunately,most sensors developed to date have been limited in detection ability and the number of components that canbe sensed. These limits may be alleviated soon with the advent of microcantilever sensors. The keyoperative factors for microcantilever sensors are simplicity, extreme high sensitivity, low cost andmodularity.

Microcantilevers are the simplest microelectromechanical systems (MEMS) (shown in Figure A.5) that canbe micromachined and mass-produced using conventional techniques. The unprecedented sensitivity ofmicrocantilever physical, chemical, and biological sensors, as demonstrated many laboratories around theworld, suggests that in the years to come, microcantilever sensors will be an integral part of many sensordevices. Microcantilever resonance response such as resonance frequency, deflection, and Q-factor undergovariation due to extremely small changes in external stimuli. Cantilever geometry determines sensitivitywhile selectivity is governed by the analyte-substrate interaction mechanism. The advantages ofmicrocantilever sensors include extreme high sensitivity, selectivity, and wide dynamic range. Demonstratedexamples include detection of ricin, nerve gas simulants, alpha particles, and explosive vapors such as TNT,RDX, and PETN. It is possible to arrange arrays of microcantilevers on one single chip for multi-target andmulti-threat detection.

Figure A.5. Microcantilevers.References(1) “Microcantilever sensors,” T. Thundat, et al., Microscale Thermophysical Engineering 1(3) 185, (1997).(2) “Bioassay of prostate specific antigen (PSA) using microcantilevers,” G. Wu, et al., Nature

Biotechnology, 19, 856-860, (2001)(3) “A chemical sensor based on a microfabricated cantilever array with simultaneous resonance frequency

and bending readout,” F.M. Battiston et. al., Sensors and Actuators B77(1-2), 122-131 (2001).(4) “Microcantilever charged-particle flux detector,” A.D. Stephan, T. Gaulden, A.D. Brown, M. Smith, L.F.

Miller, and T. Thundat, Rev. Sci. Instrum. 73(1), 26-41 (2002).

A.4. Application of Nanomaterials to High Rate Mitigation of ChemBio Threats

Chemical reactions occurring at the nanoscale continuously affect all aspects of life and technology as weknow it. Nanostructured materials are fundamental building blocks capable of catalyzing a host of chemicalreactions by virtue of their selective and tailored surface chemistries, high specific surface areas, and uniquemolecular structures.

Recent discoveries have enabled the entrapment of nano- and microstructured materials within the interior ofhigh porosity carrier networks comprised of sinter-locked micron diameter metal fibers (see Figure A.6a).This discovery greatly extends the impact and utility of evolving nanotechnologies to an ever increasingvariety of chemical processes. A low cost, high-speed paper making process is used to produce the materialsshown in Figure A6a, while the volume fraction of the metal microfibrous carrier phase and the solid reactantphase can both be varied over a wide range (independent of one another). In this manner, chemical reactionsoccurring at the surface of the entrapped phase are accommodated within a carrier of sufficient porosity tosupport required heat and mass transport to the reactive surface. This attribute is not presently available byother means, and appropriately selected nanomaterials coated onto the surface and within the pores of theentrapped phase yield sustainable reaction rates significantly higher than ever previously imagined orcommercially practiced. High volumetric reaction rates have been demonstrated for: surface catalyzedreactions, electrochemical systems, sorption processes, electrochemically assisted biological growth,filtration processes, and thermal wicking systems.

For applications in chemical and biological mitigation, microfibrous entrapped nanostructures have beendemonstrated to provide two- to four-fold higher adsorption efficiencies at as little as one-eighth the pressuredrop of a comparable packed bed of the identical sorbent. The thin layer nature of this media is also well-suited for new applications such as: foldable, pocket size chemical/biological escape hoods (see FigureA.6b); higher capacity lower pressure drop gas mask canisters (see Figure A.6c); and TSA regenerablesorbent canisters for continuous protection of buildings and structures (see Figure A.6d). Regeneration is keyto reducing life-cycle, logistical, and ownership costs. Regeneration also permits significant decreases inweight and volume, which enables extension of this technology to aircraft and transportation systems.

References(1) “Permeability of sintered microfibrous composites for heterogeneous catalysis and other chemical

processing opportunities,” D. R. Cahela and B. J. Tatarchuk, Catalysis Today 69(1-4), 33-39 (2001).(2) “Wet layup and sintering of metal-containing microfibrous composites for chemical processing

opportunities,” D. K. Harris, D. R. Cahela, and B. J. Tatarchuk, Composites: Part A 32, 1117-1126(2001).

Figure A.6:a. microfibrous entrapped b. Low pressure drop, foldable c. C1A1 & microfibrous d. Collective protection sorbent and catalyst pocket size escape hood pleated canisters sorbent/catalystcanister

A.5. Nanostructured Films for Chemical Sensing

Chemical microsensors have been developed consisting of nanoparticle oxide sensing films on MEMSdevice platforms. While the platforms provide necessary functionality for controlling the sensors andextracting response signals, the heart of each microsensor is its approximately 100- 500 Å thick (SnO2, TiO2)sensing film, which directly interacts with the environment being monitored. The devices operate bymeasuring the changes in electrical conductance that occur when gases adsorb, desorb and/or react at thesurfaces of the semiconducting oxide films. Rapid temperature modulation can be used to increase theanalytical information acquired per unit time. The roughly 100 µm x 100 µm devices (Figure A.7) can befabricated in array configurations that are tunable for different applications through the choice of sensingmaterials and operating temperatures. Due to their small size, the power consumption for the microsensors isvery low.

Sensing characteristics such as sensitivity, selectivity, stability and speed are inherently dependent on thenanostructural features of the sensing films used in the microsensors. Particle size and surface structurestrongly affect both the chemisorption and electronic properties of the films. Nanostructured oxides must bedeposited onto the SiO2 top surface of the MEMS microelements (see Figure A.7). Localized deposition ofcontrolled microstructures on these 3-dimensional devices does present significant fabrication challenges.However several methods, including seeded, reactive chemical vapor deposition (CVD), single source CVD(Figure A.8), and spinning on of sol-gels and nanoparticle suspensions, produce effective sensing oxides withparticle sizes ranging from about 10 - 100 nm. Generally, the finer films show higher sensitivities.

Application-oriented efforts supported by several agencies have demonstrated the capabilities of theconductometric microsensors in a variety of areas. Combinatorial microarray methods were employed in aDepartment of Energy (DOE) project targeted at detection of hazardous waste. An “emerging technology”project supported by the Defense Threat Reduction Agency (DTRA) has demonstrated the ability of themicrosensors in detecting low levels of molecules that simulate mustard and nerve class chemical warfareagents. It is anticipated that other nanostructured materials (wires, tubes, etc.) will enhance sensorperformance by producing new types of sensing effects as well as serving in new functional roles, such asfilters and preconcentrators, for microsensor-based microanalytical systems.

Fig. A.7. MEMS microsensor platform Fig. A.8. SEM micrograph of TiO2 film grown with CVD oxide sensing film. by CVD from titanium nitrate.

References(1) “Microhotplate platforms for chemical sensor research,” S. Semancik, R.E. Cavicchi, M.C. Wheeler, J.E.

Tiffany, G.E. Poirier, R.M. Walton, J.S. Suehle, B. Panchapakesan, and D.L. DeVoe, Sensors andActuators B 77(1-2), 579-591 (2001).

(2) “Nanoparticle engineering and control of tin oxide microstructures for chemical microsensorapplications,” B. Panchapakesan, D.L. DeVoe, M.R. Widmaier, R. Cavicchi, and S. Semancik,Nanotechnology 12(3), 336-349 (2001).

A.6. Rapid Development of Sensors for the Detection of Weapons of Mass Destruction

Computational methods for the redesign of the ligand-binding specificity of receptor proteins that canfunction as fluorescent, electrochemical or cellular biosensors have been developed and experimentallytested. The ultimate aim is to radically redesign a binding site for any ligand within a certain molecularweight range, and to apply this capability to the construction of robust, reagentless biosensors for thecontinuous, real-time detection of explosives and chemical and biological warfare agents. The combinedcomputational and experimental methodologies provide a revolutionary capability to design, construct anddeploy sensors for newly identified threats within 7-10 days.

The computational methods use the three-dimensional structure of a protein to redesign its ligand-bindingsite. An ensemble of ligand conformations are docked in place of the original ligand, and simultaneouslyreplace the amino acids at each of the 15-20 positions that define complementary surfaces with theapproximately 9000 rotamers representing all 20 possible mutations. A receptor design calculation thenidentifies the best combination of docked ligand and amino acid sequence to create a new complementarysurface. Algorithms have been developed that can solve this huge combinatorial problem (often 10100-10200

possible combinations) within 48 hrs on a 25-processor Beowulf cluster. (Time is linear with number ofprocessors.)

The periplasmic binding proteins of E. coli as the receptors are soluble, very robust, monomeric proteins thatbind a wide variety of ligands. Using novel computational methods, radically redesigned members of thisprotein superfamily have been shown to bind trinitrotoluene, or lactate, resulting in sensors that detect theseanalytes. The TNT sensor has a 1.5 nM affinity. These results demonstrate that with this new approach it ispossible to radically redesign binding specificity, and that one can attain binding sites with both a highdegree of steorespecificity and very high-affinity. The detection limit is probably better than nanomolar;experiments are under way to establish this.

The design cost for each sensor is low: ~$200/design in oligonucleotides and reagents (not accounting for thecomputational and experimental laboratory infrastructure). Once built, the biosensor proteins areinexpensive to produce. Bacterial over-expression systems will easily provide 50 mg/L for less than $20.Fluorophores necessary to label this amount of protein cost $100-300. 50 mg is more than enough proteinfor incorporation into hundreds of sensor units (e.g., at the tip of optical fibers).

Reference(1) “Converting a maltose receptor into a nascent binuclear copper oxygenase by computational design,”

D.E. Benson, A.E. Haddy, and H.W. Hellinga, Biochemistry 41(9), 3262-3269 (2002).

Receptor

Redesignedbindingsurface

Figure A.9. Receptor protein sensor concept.

A.7. Non-Invasive Monitoring of Cells for the Diagnosis of Pathogen Exposure and Infection

Nanotechnology could provide a biosensor that would be loaded into the white blood cells of soldiers. Thisbiosensor would measure the activation of leukocytes and identify early non-specific events associated withexposure to pathogens, such as alterations of mitochondrial calcium mobilization or superoxide production.In addition, the sensor would also identify events such as cytokine expression in white cells that differentiatean infection with a specific class or type of organism. These signals would be monitored non-invasivelyusing laser light directed at a laminar-flow stream of blood cells in a capillary. The system would functionlike a real-time flow cytometer, but without the need for equipment, blood drawing or sample preparation.

This approach is unique in that it will use nanosensors based on dendritic polymers. These sensors are lessthan five nanometers in diameter, and are targeted to white cells by molecules attached to their surface tospecifically bind and internalize into leukocytes. These biosensors employ non-toxic, fluorescent reportersystems. When these sensors are delivered into a cell and activated by the appropriate cellular change, theyproduce fluorescence emissions that can be interrogated by light shining on a capillary. Multispectralanalysis will allow the use of multiple sensors using dyes with different wavelength emissions. Importantly,these biosensors need to be given only once every few weeks to maintain their presence in cells, and mighteven be administered transdermally to avoid venous injections. The sensors have almost no mass and, sincethey would be located within the soldier’s cells, would avoid the need for storage.

The concept of this intracellular biosensor system in vitrowould adapt a miniaturized laser system for use as awearable monitor to non-invasively read sensor outputfrom capillaries in real time. This laser would analyze thelaminar blood flow of either a retinal or a mucosal tissue-based capillary to non-invasively sense the white cellpopulation in vivo as these cells pass through the capillary.The fluorescent signals can be sensed specifically becausethe white blood cells pass through capillaries one at a timein a laminar stream, and retinal capillaries can beinterrogated without optical interference from tissues orhemoglobin.

The sensing apparatus (Figure A.10) would involve aminiaturized optic probe placed in a “head’s up display” toshine light onto the retina, or alternatively by using a fiberoptic placed under the tongue and worn continuously formonitoring. A monitoring station also could be used wherethe individual would immobilize his or her head for aretinal scan that would allow a laser light to raster severalcapillaries simultaneously. Either type of monitor wouldbe non-invasive, and could accomplish real time

monitoring, making the system useful for identifying changes in white cell population kinetics as well as theactual activation of specific genes over time.

This interesting concept has been proposed by Dr. James R. Baker, Jr. of the University of Michigan.

Figure A.10. Illustration of the concept ofan optic probe-basedmonitoring system.

Appendix B: Glossary of Acronyms

AC blood agent, hydrogen cyanideASH/SLASH Activated solution hypchlorite/self-limitingATP Advanced Technology Program (DOC/NIST)CBRE Chemical, biological, radiological and explosiveCBW Chemical and biological warfareCK blood agent, cyanogen chlorideCNT Carbon nanotubeDMMP Dimethyl, methyl phosphonate – simulant for G chemical warfare agentsDNA Deoxyribonucleic acidDS2 Decontaminating Solution 2 [diethylenetriamine, ethylene glycol,

monomethylether, sodium hydroxide]GA nerve gas, tabun, dimethlphosphoramidocyanidate acid, ethyl esterGB nerve gas, sarin, methylphosphonofluoridic acid 1-methylethyl esterGD nerve gas, soman, methyphosphonofluoridic acid 1,2,2-trimethypropyl esterGF nerve gas, cyclohexyl sarinHD distilled mustard, vesicant, bis (2-chloroethyl) sulfideHEPA High efficiency particulate air (filter)HN-3 blister agent, 2.2.2-trichlorotriethylamineL blister agent, Lewisite [dichloro (2-chlorovinyl) arsine]LD50 lethal dosage to 50% of populationMEMS Microelectromechanical system(s)MIS Miniaturized intelligent sensingMOPP Mission oriented protective postureNBC Nuclear, biological, chemicalNEMS Nanoelectromechanical system(s)NNI National Nanotechnology Initiative (U.S. Government)NRL Naval Research LaboratoryNSET Nanoscale Science, Engineering and Technology (subcommittee of U.S.

National Science and Technology Council)ORNL Oak Ridge National LaboratoryPOL Petroleum, oil and lubricantsPR&P Protection, remediation and preventionR&D Research and developmentS&T Science and technologySBIR Small Business Innovative Research Program, U.S. GovernmentSTTR Small Business Technology Transfer Program, U.S. GovernmentTEDA TriethylenediamineTGD Thickened GDTIC Toxic industrial compoundsTSWG Technical Support Working Group (U.S. Government interagency group)VX Nerve gas, ethyl S-2-diisopropyl aminoethyl methylphosphorothiolate

Appendix C: List of Participants and Other Contributors

James R. Baker9220C MSRB III1150 W. Medical Center Dr.Ann Arbor, MI 48109-0648

Richard J. ColtonNaval Research LaboratoryCode 6170Washington, DC 20375-5342

Heidi Schreuder-GibsonU.S. Army Natick Soldier CenterKansas St. (AMSSB-RSS-MS-N)Natick, MA 01760-5020

Michael Gr¸ nzeUniversity of HeidelbergIm Neuenheimer Feld 253D-69120 HeidelbergGermany

Kenneth J. Klabunde105 Notre Dame CircleManhattan, KS 66503

Stephen LeeArmy Research Office4300 South Miami Blvd.P.O. Box 12211Research Triangle Park, NC 27709

Charles MartinUniversity of FloridaDepartment of ChemistryCLB 218, P.O. Box 117200Gainesville, FL 32611-7200

James S. MurdayNaval Research LaboratoryCode 6100Washington, DC 20375-5342

Thomas ThundatOak Ridge National LaboratoryOak Ridge, TN 37831-6123

Bruce TatarchukDept of Chem EngineeringAuburn UnivAuburn, AL 36849

Keith WardOffice of Naval ResearchCode 342800 N. Quincy St.Arlington, VA 22217-5660

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