Appendix A: Strategy for Nanotechnology-related EHS Research

Limitations of the data provided in this appendix.

This table of nanotechnology EHS projects provide the following information for each project:

Award # 2R01DK047858-10A1 Agency NIH Lead Institution University of FloridaTypeExtramural

Explanatory Notes This project will pave the way for further imaging studies in tissue engineering that may be applicable to the nanoscale.

Abstract The main criterion in assessing the therapeutic efficacy of tissue engineered construct is the successful restoration of the host's physiology. Direct and non-invasive in vivo monitoring of a construct is of great importance for the following reasons: it provides correlations between construct function and physiologic effects post-implantation in vivo; and it offers the possibility of assessing changes in construct function that may be used to develop early markers of construct failure in advance of the end-point effects. The overall objective of the proposed research is to develop a noninvasive methodology to monitor in vivo the function of an implanted tissue engineered pancreatic substitute. NMR is uniquely suited to perform such studies since it is a non-invasive modality that has the ability to probe into the intracellular metabolism of the construct, and to view the anatomy of the host at the site of implantation. NMR spectroscopic and imaging techniques can monitor several intracellular and extracellular metabolites without necessitating the introduction of foreign agents or the fixation of cells. It is our hypothesis that NMR detectable metabolic indexes can be used to monitor the function of an implanted tissue engineered pancreatic substitute and provide early indicators of implant failure while the recipient is still euglycemic. The NMR nuclei examined in this study include 1H, 19F and 31P, while the model pancreatic construct utilized is composed of mouse insulinoma #TC-tet cells or mouse islets encapsulated in alginate/poly-L- lysine/alginate beads and contained within an agarose matrix that allows for easy retrieval. The following Specific Aims are designed to address our hypothesis: Specific Aim 1: To optimize in vivo NMR signal acquisition with inductively coupled RF-coils. Specific Aim 2: To develop and validate a model of time-dependent oxygen and cell density gradients within constructs. Specific Aim 3: To non-invasively assess the function of an implanted tissue engineered pancreatic substitute and correlate that to end point physiologic events. We believe this to be a thorough, quantitative and a significant study to monitor the function of an implanted tissue engineered substitute that will identify metabolic events associated with failure ahead of its end physiologic effect. Proposed experiments are founded on strong preliminary data and we are confident that they will pave the way for further imaging studies in tissue engineering.

Award # 1Z01HD000261-09 Agency NIH Lead Institution NICHD/SBSPTypeIntramural

Explanatory Notes A critical element of this project is the development of methods and instrumentation to image tissues and study biological phenomena with nanoscale resolution.

Abstract Scientists in the Section on Biomedical Stochastic Physics (SBSP) devise quantitative theories, develop methodologies, and design instrumentation to study biological phenomena whose properties are characterized by elements of randomness in both space and time. The research focuses on developing quantitative theories applicable to quantitative optical spectroscopy and tomographic imaging of tissues. This requires analyzing different optical sources of contrast such as endogenous or exogenous fluorescent labels, absorption (e.g., hemoglobin or chromophore concentration), and/or scattering. SBSP researchers design and conduct experiments and computer simulations to validate theoretical findings. In addition, collaborations formed with other scientists at the NIH and researchers around the country and world investigate physiological sites where optical techniques might be clinically practical and offer new diagnostic knowledge and/or less morbidity than existing diagnostic methods. Biological tissues often exhibit characteristic regular features or ornamental patterns. Transition from normal tissue function to diseased tissue can be detected by quantifying irregular patterns. The degree of statistical similarities in a region of interest can carry valuable comparative information about the structural features of the tissue and can help to characterize tissue, i.e., analyze disease localization and progression. To visualize subsurface structural features of biological tissues, we have developed a user-friendly polarization imaging system that simultaneously images cross- and co-polarized light. We have developed a quantitative statistical tool, based on Pearson correlation coefficient analysis to enhance the image quality and reveal regions of high statistical similarities within the noisy tissue images. We have shown that under certain conditions, such maps of the correlation coefficient are determined by the textural character of tissues and not the choice of the reference image region, providing information on tissue structure. As an example, the subsurface texture of a demineralized tooth sample was enhanced from a noisy polarized light image. Many biological tissues (muscle, skin, white matter in brain, etc.) are known to be anisotropic, i.e., photons tend to migrate preferentially along fibers. To consider the effects of tissue anisotropy on observed characteristics of fluorescent light, we have generalized our random walk analysis of light propagation in the anisotropic turbid media for the case of a deeply embedded small fluorophore or scattering inclusion with special focus on the time-resolved measurement set-up. Our goal is to find an analytical expression for the expected change in the photon mean time of flight due to the presence of such an abnormality. Fluorophore lifetime imaging is a promising tool for studying tissue environment such as tumors. The lifetime (time for an electron to return from excited state to initial state) of a fluorophore can vary in response to changes in the immediate environment such as temperature, pH, tissue oxygen content, nutrient supply, and bioenergetic status. Mapping the lifetime and location of a fluorophore in tissue at different depths can be used to monitor such parameters. Toward this goal, we have developed a time-resolved lifetime imaging system for in vivo small animal studies that maps fluorophores lifetimes. The system consists of a single source-multiple detector array that scans the surface of the tissue. Using several source-detector separations, one is able to probe different depths of the medium. In collaboration with Dr. Capala in the Radiation Oncology Program of NCI who has developed a pH sensitive dye in the near-infrared region, we have studied the tumor environment below the skin. We have demonstrated that by using simplified back projections we are able to map near surface fluorescent lifetime in vivo. Combining this with the pre-calibrated lifetime response to pH, we have shown that biologically plausible, non-invasive, quantification of pH in mouse tumors can be determined. The oncology community is testing a number of novel targeted approaches for use against a variety of cancers. With regard to monitoring vasculature, it is desirable to develop and assess noninvasive and quantitative techniques that can not only monitor structural changes, but can also assess the functional characteristics or the metabolic status of the tumor. We are testing three potential noninvasive imaging techniques to monitor patients undergoing an experimental therapy: infrared thermal imaging (thermography), laser Doppler imaging (LDI) and multi-spectral imaging. These imaging techniques are being tested on subjects with Kaposis sarcoma (KS), a highly vascular tumor that occurs frequently among people infected with acquired immunodeficiency syndrome (AIDS). Cutaneous KS lesions are easily accessible for noninvasive techniques that involve imaging of tumor vasculature, and they thus represent a tumor model in which to assess certain parameters of angiogenesis. The KS studies are ongoing clinical trials under four different NCI protocols. Thermography graphically depicts temperature gradients over a given body surface area at a given time. LDI can more directly measure the net blood velocity of small blood vessels in tissue, which generally increases as blood supply increases during angiogenesis. NIRS is most closely related to visual assessment. In collaboration with Dr. Demos at the Lawrence Livermore National Laboratory, a portable spectral imaging system was designed that captures images with a high-resolution CCD camera at six near-infrared wavelengths (700, 750, 800, 850, 900, and 1000 nm). Collected intensity images are used in a mathematical optical model of skin containing two layers: an epidermis and much thicker, highly scattering dermis. Each layer contains major chromophores that determine absorption in the corresponding layer and the layers together determine the total reflectance of the skin. Local variations in melanin, oxygenated hemoglobin (HbO2), and blood volume are reconstructed through a multivariate analysis. High-resolution confocal laser microscopy is an intensively active field in modern bioimaging technologies because this technique provides sharp, high-magnification, three dimensional imaging with submicron resolution by non-invasive optical sectioning and rejection of out-of-focus information. We have developed a simple fiber-optic confocal microscope with nanoscale depth resolution beyond the diffraction barrier. It is based on combining the advanced properties of a simple apertureless single-mode-fiber confocal microscope design that provides highly sensitive diffraction-free Gaussian point light source/receiver, and a differential confocal microscope approach in which the sharp diffraction free slope of the axial confocal response curve is exploited. We have also developed an algorithm to enhance diffraction-limited images and obtain information on features smaller than the diffraction limit. Our algorithm tries to infer the best estimate of an object based on the diffraction-limited input image. Imaging an object with a diffraction-limited lens introduces in a blurred image, where neighboring pixels on the camera are correlated. The correlations between pixels are determined by the point spread function (PSF) of a diffraction-limited lens.

Award # 1R01MH071830-01A2 Agency NIH Lead Institution Washington State UniversityTypeExtramural

Explanatory Notes In combination with other intracellular measurement techniques, which may involve nanoparticles like quantum dots, this technique will improve ways of correlating electrophysiological measurements with intracellular biochemical or genetic pathway measurements not currently done.

Abstract The impact of sleep loss and sleep disorders on the health, social and economic well being of Americans is enormous. Yet our knowledge about the control and function of sleep remains severely limited, and based largely on studies where subjects are tethered, with significant behavioral side- effects. Thus, compact, implantable recording systems have become a major factor in sleep studies, especially in small transgenic mouse models where tethering is not practical. Existing telemetry systems are severely limited in the amount of information they can gather, and are not conducive for most studies. To address this need, we have assembled an interdisciplinary team to address four specific aims. First, we will develop a flexible electrode array that can be chronically implanted on the cortical surface of neural tissue. Traditional rigid electrode arrays require large skull openings. The flexible array has the advantage of minimal tissue trauma because only a slot in the skull is needed to insert the flexible array. One major drawback of multi-channel recordings comes from the large number of wires required for 16 to 256 or more channels of electrophysiology. Signals multiplexing can help, but available components including amplifiers, filters and multiplexers are comparatively large. Thus, our second aim will develop a miniature analog-system-on-a-chip, including preamplifiers, filters, multiplexer and 16 bit analog-to-digital converter for sampling 16 to 256 channels up to 32 kHz per channel. The chip will initially require only 5 wires for a serial digital connection and will weigh less than 1 gram. Our third aim will be to implement high speed wireless technology to allow the serial digital data to be transmitted directly from the acquisition chip to our computer interface card without the use of wires. Recent developments in digital wireless technology have allowed unprecedented data rates through transmitted signals. However, in order for wireless technology to be effective, our fourth aim will focus on an implantable power source enabling fully untethered recordings. Different power source technologies will be explored including battery and magnetic inductance. The technologies developed within this proposal will provide powerful new tools for neuroscience when many channels of electrophysiology, EEC, SEP and multi-unit electrodes are required in freely behaving animals, especially small rodents. The new technology is particularly important for wireless medical devices that require many channels with high data rates.

Award # 1R21MH074703-01A1 Agency NIH Lead Institution Johns Hopkins UniversityTypeExtramural

Explanatory Notes This research is in neural micro/nano systems within a biomedical instrumentation laboratory developing technologies for recording from neurons or the brain and developing interfaces, at molecular/cellular and at the systems level. Micro- and nanotechnology are utilized for the fabrication of sensors.

Abstract This is an interdisciplinary, innovative technology research and demonstration project to develop the next generation of neural probes for implanted recording. Current neural probes record electrical signals with the use of multiple silicon micromachined electrodes. In an advancement in this field, supported by previous NIH funding, we have demonstrated miniature neurochemical sensors and developed the specialized VLSI integrated circuitry needed to enable chemical measurements from multiple electrodes in a microprobe assembly. The next challenge is to research methods to harvest power to energize the implanted sensor and circuitry. Towards this goal, we propose two innovative technologies 1) the development of a rechargeable, microbattery system capable of sustaining power to the sensor and circuitry, 2) development of a novel VLSI wireless power harvesting circuit to energize the battery. Our other aims are to 3) develop an integrated probe with neurochemical sensor, VLSI wireless interface, power harvesting circuit and microbattery, and 4) evaluate the probe in a model of global ischemic brain injury. This research contributes to our long term goal to build fully implantable, autonomous microprobes, without any tethering, for neurochemical recording in chronically instrumented and tether less animals. A fully self-powered implanted neural microprobe system will be an enabling tool in the hands of neuroscientists interested in recording neural activity from animal models of brain function or brain disorders with the use of microelectrode arrays.

Award # 1R21MH078822-01 Agency NIH Lead Institution University of ChicagoTypeExtramural

Explanatory Notes This work supports nano- to micro-scale fluorescence measurements of electric fields in molecules.

Abstract The long term objective of this project is the development of an optical detection system based on surface plasmon resonance to study the dynamics of membrane proteins with special emphasis in voltage gated ion channels such as the Na and K channels that are responsible for the generation and propagation of the nerve impulse. Channel proteins are labeled in specific sites with fluorescent probes using cysteine chemistry and the fluorescence is detected by the proposed optical setup. Fluorescence changes, produced by quenching or energy transfer are indicators of local environmental changes and thus they follow conformational changes within the protein as the channel undergoes transitions from the closed to the open state. The optical apparatus uses a hemispherical lens that couples an incoming laser beam on a glass chip that has a thin (50 nm) siver layer where the biological preparation lies separated by a thin (10 nm) layer of silicon oxide. The correct angle of excitation induces plasmon resonance in the metal and enhances the fluorescence of fluorophores labeling the channel. The detection is done from the biological preparation side or from the excitation side. In the second case the signal to noise ratio is expected to be much larger because the coupled emission comes from a region limited to 20 nm and, as it is directional, a specially designed optics collects most of the light on a photodetector. The testing of the optical sytem is done on labeled ion channels expressed in mammalian cells or in supported bilayers. In the second case, the supported bilayer is made with liposomes containing purified labeled channels. The voltage across the bilayer is changed taking advantage of the silver layer of the plasmon chip. A modification of the optical system is also proposed to image the biological preparation to follow the time course of the fluorescence of individual molecules in response to voltage pulses that change the conformation of the channel. The understanding of conformational dynamics of channel proteins is a crucial step in the design of drugs or therapies needed to ameliorate or cure several neurological deseases produced by abnormal function of ion channels. The optical system developed in this application is aimed at developing a new microscope that is especially designed to detect conformational changes of ion channels with improved resolution, higher sensitivity and improved rejection of spurious fluorescence than presently available devices.

Award # 1R43MH076318-01 Agency NIH Lead Institution Pinnacle Technology, Inc.TypeExtramural

Explanatory Notes In combination with other intracellular measurement techniques, which may involve nanoparticles like quantum dots, this technique will improve ways of correlating electrophysiological measurements with intracellular biochemical or genetic pathway measurements in ways not currently done.

Abstract The long term objective of this project is to develop, validate and commercialize wireless, head mounted, turnkey, EEG/EMG systems with an integrated biosensor for rats and mice. A further objective is to develop a 76 uM glucose biosensor for direct measurement of brain glucose levels in rats and mice. The specific aims of this Phase I project are to develop and test a 76 uM glucose biosensor, a tethered EEG/EMG/Biosensor solution for mice and a wireless solution for rats. To reach these objectives, Pinnacle Technology, Northwestern University and the University of Kansas are building on past successes in the design of glutamate biosensors, wireless potentiostats for rats, and tethered EEG/EMG systems for mice. These products were developed in separate collaborations and are currently being commercialized. Products to be introduced include: a tethered system for mice, a wireless system for rats, and ultimately a fully wireless system for mice. Commercial applications include sleep research, behavioral research and drug screening. Technological innovations include biosensor design, turnkey head mount design, advanced electronics design, and advanced low power radio frequency design. The ability to measure glucose from specific brain areas in vivo while simultaneously recording sleep in rodents will give researchers the ability to better examine the functioning of specific sites within the brain during the sleep process as well as leverage the advantages conferred by using rat and mouse models for research. At the moment, it is not possible to concurrently study sleep and glucose regulation in a mouse model and there is only one published account where it has been attempted in the rat. The ability to instantly record glucose levels in a sleeping mouse or rat, and correlate that activity with EEG/EMG, will be valuable to researchers studying sleep and metabolism. The investigation of glucose in a mouse model will open up new avenues of research with genetic mutations available in species such as the NIRKO mouse (brain/neuron-specific insulin receptor knockout) which may have altered glucose responses during sleep and provide clues as to how sleep and metabolism are linked.

Award # 5R21EB005390-02 Agency NIH Lead Institution TDA Research, Inc.TypeExtramural

Explanatory Notes This project strives to improve magnetic resonance techniques for cellular and molecular imaging through the development of new contrast agents based on nanotubes and magnetic nanomaterials. Biocompatibility and physical characterization studies are central components.

Abstract This project will investigate a new class of potent magnetic resonance imaging (MRI) contrast agents based on cut carbon nanotubes filled with magnetic nanomaterials. These materials will function as protective nanocapsules for the delivery of magnetic materials and offer orders-of-magnitude improvement in MR contrast enhancement, vital to achieving the goal of cellular and molecular imaging with MRI. Synthetic efforts towards filling the cut nanotubes and derivatizing their outer surfaces for water solubility and biocompatibility will be central. Physical characterization of this new class of MRI contrast agent, including relaxometry by NMRD will provide insight into their relaxation mechanisms and offer avenues for further improvement. Collaboration with experts in toxicology and radiology will establish their suitability for eventual clinical investigations. The new platform technology to be created in this project offers a unique paradigm in MRI contrast enhancement useful for broad applications as both an implement in the medical research toolkit as well as for clinically relevant MRI contrast agents for the detection and improved treatment of disease.

Award # 5R21EB005365-02 Agency NIH Lead Institution Sandia National LaboratoryTypeExtramural

Explanatory Notes This effort to optimize the design, delivery, and imaging of the novel nanoprobes will lead to the development and improvement of methods to detect and characterize nanomaterials.

Abstract The major goal of this application is to synthesize new ceramic nanoprobes for bio-imaging that are highly fluorescent, bio-compatible, non-toxic, and tunable. This will be accomplished through a cross-discipinary venture between: (i) a group of material scientists and chemists from Sandia National Laboratories (Sandia) who are new to the NIH but have proven expertise in nanoparticle synthesis and biofurctionalization and (ii) a group of NIH-funded cell biologists from the University of New Mexico's School of Medicine (UNM-SOM) who have expertise in imaging cell signaling and trafficking pathways. The Sandia chemistry group will work concurrently towards two goals: (i) the synthesis of luminescent ceramic nanoprobes and (ii) innovations in functionalization that will deliver these probes to desired cellular targets. Initial synthetic efforts will focus on generating analogs of naturally occurring fluorescent (NOF) minerals as well as developing tailor-made nanoparticles doped with lanthanide cations for enhanced fluorescence. A library of novel compounds and synthetic pathways previously developed in the Sandia laboratory for nanoparticle synthesis will provide a unique knowledge base to initiate the development of useful luminescent ceramic nanoprobes. Probe functionalization will rely on PEG-phospholipids that allow for further bio-conjugation with proteins, peptides, small organic molecules/ligands and also with poly(arginine)-based transporters for transmembrane delivery. The UNM biology group will provide bioma terials to assist in the functionalization of the nanoprobes and will image probe delivery and specificity for cellular targets using live cell multispectral confocal microscopy. Preliminary interdisciplinary studies have validated the basic approaches for the synthesis of NOF nanoprobes and the biodelivery and imaging of nanoparticles. Intensive work to optimize the design, delivery, and imaging of these new nanoprobes is expected to achieve the RFA's goal of "increases in the sensitivity and specificity of molecular probes" for imaging. Results from this award will set the stage for in vivo studies whose goals will be: (i) to detect cancer sites, inflammation, and other disease processes and (ii) to deliver and release drugs at disease sites by further manipulation of the functionalization chemistry. All of the innovations uncovered during the preparation of these nanoprobes will be shared in order to benefit medical research applications beyond those proposed in this investigation.

Award # 5R21EB005364-02 Agency NIH Lead Institution Montana State UniversityTypeExtramural

Explanatory Notes This project aims to achieve a one-order-of-magnitude increase in the ability to detect and image molecular level events in vitro and in vivo. Improvement to techniques for detecting nano-particle contrast agents supports metrology methods to detect nanomaterials.

Abstract Our overall goal is to create and test a new generation of cell- targeted MRI contrast agents. The aim will be to achieve at least an order of magnitude increase in improvement in the ability to detect and image molecular level events in vitro and in vivo with broad applications in medicine. This proposal is a multidisciplinary effort, combining established expertise in cardiovascular, vascular biology, MRI, virology, synthetic inorganic and nano-materials chemistry. The overall approach will combine the use of non-infectious virus and other protein cage architectures for multivalent display of cell-specific targeting ligands, high performance metal based imaging agents, for functional and cellular imaging using MRI. The advantage of this approach is a substantial increase in rotational correlation time due to the size of the virus architecture in combination with high-density presentation of targeting ligands and metal binding sites with free access to water. The specific objectives of this proposal are (1) synthesis of protein cage architectures with high-density presentation of both cell targeting ligands and high magnetic moment materials, (ii) controlled fabrication of protein cage nano-particle clusters incorporating functionalized cell targeting ligands and MRI contrast agents, and (Hi) in vitro and in vivo MRI evaluation of functionalized protein cage architectures including improved MRI techniques for detecting nano-particle contrast agents. Creation and evaluation of these materials as functional MR contrast agents using state-of the-art facilities will provide rapid and direct feedback for an iterative process to create the next generation of high performance functional MRI contrast agents.

Award # 5R21EB005394-02 Agency NIH Lead Institution University of Texas-MD AndersonTypeExtramural

Explanatory Notes This project targets the development of ultra-sensitive magnetic resonance imaging probes for cancer molecular imaging applications. To evaluate the safety, biocompatibility, and effectiveness of probe materials (which include nanostructured composites), new fundamental methods to detect and characterize the probe materials will be developed.

Abstract The objective of this research is to develop ultra-sensitive magnetic resonance imaging (MRI) probes based on MFe2O4 (M=Fe, Co, Mn)-loaded polymer micelles for cancer molecular imaging applications. MRI is a powerful clinical imaging modality that has wide applications in the non-invasive diagnosis and post-therapy assessment for cancer and other diseases. Currently, low sensitivity of detection (approximately 10[-4] M) of conventional MR contrast agents severely limits their applications in monitoring molecular processes in vivo. In this application, we will investigate MFe2O4 (M=Fe, Co, Mn)-loaded polymer micelles as a new multifunctional platform of MRI probes with high sensitivity and biological specificity. Recently, monodisperse MFe2O4 nanocrystals have been successfully developed with fine tuning of particle size below 20 nm. These nanocrystaline materials have demonstrated unique super-paramagnetic (e.g. CoFe2O4) or ferromagnetic (e.g. CoFe2O4) properties. Herein we propose to develop a novel nanocomposite construct consisting of inorganic MFe2O4 nanoparticles loaded inside the hydrophobic cores of amphiphilic polymer micelles. We hypothesize that MFe2O4 -loaded polymer micelles will provide a safe and ultra-sensitive MRI probe for molecular imaging applications. In one specific application, we will functionalize micelle surface with a cyclic Arg-Gly-Asp (cRGD) peptide and examine the imaging of alpha(v)beta(3) receptors on the angiogenic endothelial cells in the tumor neo-vasculature. The specific aims are: (1) Investigate the MR relaxivity and sensitivity of MFe2O4 -loaded polymer micelles; (2) Evaluate the safety and biocompatibility of the MFe2O4 -loaded polymer micelles; and (3) Evaluate the effectiveness of cRGD-functionalized, MFe2O4 -loaded polymer micelles in imaging alpha(v)beta(3) receptors in rabbit VX-2 tumors. This R21 funding will provide critical support to establish MFe2O4 -loaded polymer micelles as a safe and sensitive MR imaging probe for in vivo molecular imaging. If successfully established, these MR probes will provide a powerful technology platform that can exploit the plethora of molecular targets identified in cancer biology for early cancer detection and/or non-invasive assessment of post-therapy outcome.

Award # 3P01DK060564-05S1 Agency NIH Lead Institution Univ of Massachusetts Medical SchoolTypeExtramural

Explanatory Notes This program project combines biochemical, structural and imaging approaches to study proteins by effectively combining diverse experimental techniques with powerful deconvolution algorithms to achieve resolution at the nanometer level.

Abstract Multiprotein complexes that mediate crucial cellular functions, such as signal transduction and membrane traffic, are assembled at the interface of the membrane and the cytosol. The apposition of multiprotein complexes on membrane-cytosol interfaces is achieved in several ways. The best understood manner involves the anchoring of the complex around one or several integral membrane proteins, as is for example the case of complexes of receptor tyrosine kinases and cytosolic signaling proteins. Other multiprotein assemblies are anchored on the polar head groups of phosphoinositides. For example, coat proteins involved in membrane budding assemble onto phospholipid bilayers, and signaling complexes can specifically assemble onto 3' phosphoinositides. The molecular basis for the formation of such phospholipid-based assemblies is poorly understood. This Program Project combines biochemical, structural and imaging approaches to address the question of how multiprotein assemblies are organized around 3' phosphoinositides. The Program Project format is required to effectively combine divergent techniques, which include X-ray crystallography, live cell imaging using digital imaging microscopy with laser-based illumination, and powerful deconvolution algorithms to achieve resolution at the nanometer level. Two model systems will be studied. First, the Czech group will study subcellular localizations of PtdIns(3)P, PtdIns(4,5)P2 and PtdIns(3,4,5)P3 and the multiprotein signaling complexes composed of GRPI, ARF-GTPase, and GRSPI, which are anchored around Ptdins(3,4,5)P3. Second, the Corvera group will study an endosome fusion complex containing EEA1, RabS and calmodulin, which is anchored around PtdIns(3)P. Specific questions to be addressed include: is the interaction of a protein with a phospholipid head group necessary and sufficient to determine its localization to specific regions of the membrane? For this, GFP-fusions of the proteins cited above will be used to determine the subcellular distributions of 3' phosphoinositides in fixed and live cells relative both to the kinases that produce them and to the other components of the complex. As a further means to determine the mechanisms by which these complexes function, the Lambright group will seek to solve the crystal structures of individual protein components as well as of their complexes with lipid head groups. Such structures will be important in defining the spatial topographies of signaling complexes relative to the membranes to which they are bound. The activities in the three projects are highly integrated and collaborative, and are supported by an Imaging Core rated as outstanding in the previous review.

Award # 5R01DK068399-02 Agency NIH Lead Institution Johns Hopkins UniversityTypeExtramural

Explanatory Notes Project supports the synthesis and characterization of nanomaterials targeted for biological study. Nanomaterials are characterized at the tissular, cellular, and subcellular level by various techniques including electron microscopy.

Abstract Liver represents one of the most important targets for gene medicine applications because of the access of the transgene product to systemic circulation, and because it is the site of many metabolic genetic disorders, viral infection and malignancies. A critical barrier in realizing the potential of liver-targeted gene transfer is the development of a safe and efficient gene carrier in combination with a feasible and efficient administration route. To address this issue, we are developing a nanoparticle gene delivery system based on chitosan, which is a biodegradable, biocompatible, and structurally versatile natural polymer. Our recent 'proof-of-concept' experiments have shown that intrabiliary infusion of nanoparticles achieves high levels of transgene expression in rat liver. In this proposal, we build on this finding and hypothesize that high, persistent and liver-targeted transgene expression can be achieved by the systematic optimization of the structure and physicochemical properties of chitosan-DNA nanoparticles and the intrabiliary infusion parameters. The goal of the following set of four specific aims is to experimentally verify this hypothesis and to elucidate its underlying mechanisms: (1). To synthesize and characterize novel chitosan-DNA nanoparticles with optimal complex stability, colloidal stability and hepatocyte-targeting capability. Structure- property-transfection activity relationships will be established; (2). To optimize administration parameters for intrabiliary infusion of chitosan-DNA nanoparticles. Four leading nanoparticle candidates from Aim 1 will be used to evaluate infusion parameters that could significantly affect in vivo transgene expression through intrabiliary infusion; (3). To characterize the nanoparticle/DNA delivery process at the tissue level, at the cellular level in the liver, and at the subcellular level by quantitative PCR, immunofluorescence staining and EM. The information will provide insight to the detailed mechanism of nanoparticle transport and gene delivery through intrabiliary infusion; (4). To validate the gene delivery strategies developed in Aims 1-3 by producing two types of gene product: the systemic circulation of IFN-alpha2b in normal rat, and the correction of a congenital metabolic defect in the Gunn rat mediated by the hUGT1 A1 gene. These experiments will validate our proposed gene delivery strategy and demonstrate its broad applicability for production of proteins intended for systemic distribution and for localized liver-specific diseases.

Award # 5R21MH075059-02 Agency NIH Lead Institution University of California-IrvineTypeExtramural

Explanatory Notes In combination with other intracellular measurement techniques, which may involve nanoparticles like quantum dots, this technique will improve ways of correlating electrophysiological measurements with intracellular biochemical or genetic pathway measurements not currently done.

Abstract The long-term objective of this project is to understand how morphogen gradients pattern the cerebral cortex and other tissues during development. Morphogen gradients are fundamental to animal development, and morphogen defects are primary causes of human birth defects and malformations of the cortex. Nonetheless, tremendous controversy remains about the mechanisms by which morphogen gradients act, which limits our understanding of these human disorders. For the most part, this controversy revolves around a single issue - the inability to distinguish morphogen activities that do not depend on cell-cell communication (the "classical" model) from those that do. To date, insight into this issue has relied on heroic studies using traditional dissociated cell cultures, which are limited both in terms of experimental efficiency and as models of natural morphogen gradients. However, a microfluidic culture device has the potential to address these limitations. This microscale device generates precise and continuous biomolecular gradients with different profiles onto cells, and is designed for time-lapse microscopy. These features should provide several biological and practical advantages over traditional cultures for modeling and studying morphogen gradients. Preliminary studies with cortical precursor cells (CPCs) confirm the promise of this system, but have also identified device design features that need to be optimized in order to answer the basic question driving this proposal - which CPC responses in the normal cortex are determined solely by extracellular morphogen concentration, and which are not? The goals of this R21 proposal are to fabricate optimized microfluidic devices for culturing CPCs (Aim 1) and to develop real time assays with single cell resolution in order to efficiently study CPC responses as functions of morphogen concentration, gradient profile, cell density, and time (Aim 2). To achieve these goals, a multidisciplinary team with primary expertise in bioengineering (Noo Li Jeon, the developer of the original gradient-generating device), morphogen gradients (Arthur Lander) and cortical development (Edwin Monuki) has been assembled. If successful, this proposal should not only advance our understanding of cortical development and malformations, and of morphogen gradients in general, but should also provide a versatile microfluidic tool with a wide range of basic and clinical applications.

Award # Agency NIST Lead Institution NISTTypeIntramural

Explanatory Notes Single-photon spectroscopic techniques are being developed to assess the purity and chemical composition of nano-EHS relevant nanomaterials in complex matrices such as tissues or fluids.

Abstract Multiple spectroscopic techniques are being developed to assess the purity and chemical composition of nano-EHS relevant nanomaterials in complex matrices such as tissues or fluids. These will exploit single or few photon sources and detectors and very small interaction volumes. As a result, the technical challenge is a signal to noise problem, not a diffusion limit problem. This will allow detection of flourescence at extremely low concentrations, which can be significant for biological agents for which on a few cells are at a toxic level.

Award # Agency NIST Lead Institution NISTTypeIntramural

Explanatory Notes This project will impact the development of rapid spectroscopic techniques for detecting chemical and biological agents. Such work furthers the ability to detect nanomaterials.

Abstract Knowledge of the photon quantum state is exploited to improve measurement uncertainty from N-1/2 to N-1, thereby increasing the resolution beyond classical limits and/or decreasing the measurement time. This will impact development of rapid spectroscopic techniques for detecting chemical and biological agents.

Award # Agency NIST Lead Institution NISTTypeIntramural

Explanatory Notes New measurement approaches to study novel nanostructured material are a principle component of this project, and support the development of methods to detect nanomaterials.

Abstract We will develop new metrologies and nanostructured materials to enable roomtemperature, high sensitivity thin film magnetic field sensors. These devices will be incorporated into systems for biomedical, homeland security, and magnetic field mapping applications. Room temperature magnetic field sensors are currently limited to relatively high fields (greater than 1 nanotesla). Measurement and mapping of ultra-low magnetic fields (on the order of 1 picotesla) will revolutionize many technologies including DNA sequencing and pathogen detection using sensors for molecular nanomagnet tracers, non-invasive measurement of iron overload in the body, and biohazard detection with sensor arrays for magnetic bead chemical tags.

Award # Agency NIST Lead Institution NISTTypeIntramural

Explanatory Notes This project seeks to develop a superresolution optical microscopy platform. This will enable in-situ characterization of organic and biological materials and supports the development of methods to detect nanomaterials.

Abstract The scientific and metrology underpinnings necessary for the realization and operation of superresolution light microscopy in real world applications will be developed and then used to design and build a flexible superresolution optical microscopy platform. When combined with vector point spread function engineering, this platform will establish the state-of-the-art in optical diagnostics for in-situ, characterization of organic and biological materials, and will ultimately represent a field upgrade for conventional microscopy.

Award # Agency NIST Lead Institution NISTTypeIntramural

Explanatory Notes This project iinvestigates use of semiconductor quantum nanowires in a variety of sectors. Metrology efforts support the development of methods to detect nanomaterials.

Abstract Semiconductor quantum nanowires (SQNW) offer new revolutionary applications in biological/chemical sensors, in vivo biomedical diagnostics and therapies. SQNW lasers with emission apertures roughly 20-100 nm in diameter (about the size of a virus) could lead to ultra high resolution microscopy and cellular-level imaging. The high surface-area-to-volume ratio, coupled with the electrical sensitivity, may lead to a compact ‘electronic noise’ for chemical and/or biological agents. Besides providing new nanometrology tools for material science and biotechnology, and new sensor capabilities for homeland security needs, our efforts will also result in new nanoscale data and best practices for these areas.

Award # Agency NIST Lead Institution NISTTypeIntramural

Explanatory Notes This project is developing new techniques for rapid acquisition of chemical information with high spatial resolution.

Abstract Researchers have developed a method for obtaining three-dimensional broadband vibrational spectra in a microscopic modality. The measured spectra are similar to those obtained from Raman but are acquired with approximately 1,000 times greater efficiency. This new technique is a broadband variant of a well-established nonlinear spectroscopy—Coherent anti-Stokes Raman scattering (CARS). CARS microscopy is becoming increasingly important in biological imaging. Ordinarily, optical microscopy requires researchers to stain (visible or fluorescent) for specific structures or metabolic states. This type of approach cannot be used for all cellular components. CARS microscopy provides a partial solution to this because it is non-invasive and has selective chemical sensitivity; however, its full potential for species-selective imaging usually is limited by restricted spectral bandwidth.

Award # Agency NIST Lead Institution NISTTypeIntramural

Explanatory Notes A wide range of ion, electron, and X-ray spectroscopies, microscopies, and microanalysis techniques are under exploration for the detection and characterization of nanomaterials.

Abstract Cutting-edge electron and ion-based microscopies as well as mass spectrometry techniques will be used for determining nanomaterial shape and structure. Standards for validation of these methods will be developed. Existing techniques for chemical and structural characterization with atomic resolution will be leveraged, and methods that provide information about the chemical structure of individual nanoparticles and the chemical structure of agglomerates of nanoparticles will be developed. Applicable approaches include a range of ion, electron and X-ray spectroscopies, microscopies and microanalysis techniques.

Award # Agency NIST Lead Institution NISTTypeIntramural

Explanatory Notes This program supports the development of calibration techniques which will allow accurate detection and measurement of nanomaterials.

Abstract For the optics and semiconductor industries, NIST developed a calibrated atomic force microscope, which is calibrated against the wavelength of light in all three coordinate axes. This device calibrates three-dimensional artifacts that, in turn, will be used to calibrate scanning probe microscopes. The semiconductor industry relies on NIST to provide accurate surface measurements of step heights and pitch spacings. For the data storage industry, NIST calibrations support line edge roughness measurements. This program is responsible for certifying Standard Reference Materials for roughness and for calibration of the magnification of scanning electron microscopes.

Award # Agency NIST Lead Institution NISTTypeIntramural

Explanatory Notes Investigations on the possible optical measurements of nanometer-sized features supports the development of methods to detect nanomaterials.

Abstract Optical microscopy will be advanced to unprecedented levels of performance through theoretical and experimental development of a new technique called "scatterfield optical imaging". This new method promises to make possible optical measurements of nanometer-sized features using high-throughput, low cost optical methods with the potential for an enormous impact on innovation and quality control in semiconductor manufacturing and nanotechnology as well as providing the measurement basis for new calibration standards well beyond the state-of-the-art. The new microscopy methods proposed here will enable a significant leap in the sensitivity to geometrical changes of the sample on the order of 1 nm. This method could be developed to image molecular structures.

Award # Agency NIST Lead Institution NISTTypeIntramural

Explanatory Notes This project seeks to develop a comprehensive set of metrological tools for measuring nanoparticles in biomaterials and bio-relevant media.

Abstract This program will address critical issues related to the complete cycle of nanoparticles within biosystems. It will accomplish this by developing a comprehensive set of metrological tools for assessing the dimensional and compositional properties of nanoparticles in biomaterials and bio-relevant media. This includes dimensional metrology to obtain precise structural information on nanoparticles combined with image enhancing simulations, and surface chemical characterization methods with atomic resolution.

Award # 0528873 Agency NSF Lead Institution University South CarolinaTypeExtramural

Explanatory Notes The advancement of nano investigative techniques ( including a range of microscopy techniques) are a critical component of this project.

Abstract The project will use nanofabrication methods (such as pulsed laser deposition) and advanced nano investigative techniques (such as SEAM, SPM, TEM, EPMA, EDS, HR-SEM, AFM, XRD) to grow miniaturized thin-film active sensor arrays on typical structural materials for use in advanced structural health monitoring applications. Appropriate buffer interfaces to ensure durable adherence of the ferroelectric film to the structural material and coherent epitaxial growth will be developed. High-performance environmentally friendly ferroelectric compositions will be developed. Modeling and analysis will be used in developing the buffered interface, the nano-fabrication processing methods, and the Lamb/Rayleigh wave phased-array algorithms for structural health monitoring applications of these new devices. The highly interdisciplinary character of the proposal is covered by a sensors small team with members from the disciplines of material science, electrical engineering, mechanical engineering, and physics, spanning over four universities (Louisiana State University, Pennsylvania State University, University of South Carolina, University of Texas at San Antonio), of which one is a Hispanic-serving institution (HSI): The project will employed analytical modeling, numerical simulation, and experimental validation. It will build on the preliminary results obtained by the individual investigators. In additional to technical activities, the project will address important sensors education and outreach activities.

Award # 0547273 Agency NSF Lead Institution Duke UniversityTypeExtramural

Explanatory Notes Metrology efforts support the development or improvement of methods to detect nanomaterials.

Abstract The objective of this research is to enable simultaneous sensing of multiple physical phenomena for application to aerosol detection, homeland security, and medical field-diagnostic tools, for example. The approach is to use hybrid nanomaterials in a monolithic, semiconductor-based heterostructure for multi-functional sensors. Two classes of quantum-confined semiconductor nanomaterials are considered; colloidal quantum dots synthesized by chemical reactions and Stranski-Krastanow quantum dots grown by strained-layer epitaxy. The grand challenges to be addressed are: i) synthesis of colloidal quantum dot/polymer nanocomposite thin-films for optoelectronic device active regions, and ii) synthesis of nanocomposite thin-films featuring disparate nanomaterials embedded in polymers or semiconductors with atomically-sharp interfaces, dopant incorporation capability, and electrical contact layers. A multi-spectral photodiode array synthesized using a hybrid nanomaterial growth system will be demonstrated to culminate the proposed project.

Broader Impacts
The investigation of hybrid nanomaterial device heterostructures for multi-functional sensors with emphasis on environmental applications addresses two 2005 NSF Priority Areas, nanoscale science/engineering and environmental biocomplexity. The proposed hybrid nanomaterial growth system enhances research infrastructure by establishing synthesis techniques for atomically-thin nanocomposite layers. The proposed activities advance discovery while promoting learning by enabling undergraduate research and enhancing the Duke University Electrical and Computer Engineering photonics graduate curriculum. The proposed activities also broaden the participation of underrepresented minorities in science and engineering through the Student Engineers Network, Strengthening Opportunities in Research Saturday Academy and Historically Black College and University student recruitment. Finally, the broad dissemination of results from the proposed activities will be accomplished through scientific publications and the NSF-supported TeachEngineering.com digital library.

Award # 0448796 Agency NSF Lead Institution Boston UniversityTypeExtramural

Explanatory Notes Metrology efforts support the development or improvement of methods to detect nanomaterials.

Abstract The primary objective of this CAREER project is to enable rapid, accurate imaging of thermal and mechanical properties on micrometer and nanometer length scales, thereby contributing to the effort to improve the performance and reliability of micron scale systems and in the effort to understand and control the thermal and mechanical behavior of materials at the nanoscale. The PI develops novel photoacoustic and photothermal (PA/PT) measurement capabilities for the noncontact and nondestructive imaging of surface properties and subsurface defects at the nanoscale, along with an understanding of how the measured quantities relate to the thermo-mechanical properties of the target material. A technique for producing highly localized heat sources and probes for PA/PT imaging is explored, with the goal of pushing the lateral resolution of PA/PT microscopy to the nanoscale regime. This novel imaging modality makes use of the high absorption and local field enhancement around nanoparticles excited at the plasmon resonance frequency, and will have a broad impact in the quest to understand and characterize material behavior at the nanoscale. Next, A high-resolution photoacoustic microscopy system is developed which uses a high-frequency (GHz) modulated excitation source. Improvements in signal to noise ratio over pulsed systems are expected through bandwidth reduction and pulse coding techniques, expanding the range of applications for which this NDE technique is suitable. The final thrust area in this proposal focuses on the modeling of laser generation of acoustic and thermal waves in complex materials systems, an area which is essential for the interpretation of thermal and acoustic signals in these systems, and for accurate inversion of these signals to obtain material property information. The research results will have direct applications in nanofabrication: for online monitoring of the fabrication process as well as in the measurement of the fundamental properties of "as-fabricated" materials systems. This project supports both graduate and undergraduate researchers, and trains these students in a wide cross-section of engineering science that this project draws upon including NDE, applied optics, elastic wave propagation, and nanoscale engineering.

This CAREER project supports the development and implementation of the Learning Experiences for New Scientists (LENS) program in which academically at-risk 7th and 8th grade students come to Boston University for a week of hands on demonstrations and problem solving activities. This program targets students at a critical time in the development of science skills, and is aimed at reducing the number of students graduating from high school who lack basic proficiency in science and math. The multi-media presentations developed for the LENS program are placed on the Web to disseminate to other educators, and are made available for other outreach programs through the Learning Resource Network (LERNet) program at Boston University. The PI has arranged for a graduate student to work at Lawrence Livermore National Lab for one summer under this project. This opportunity allows the student to interact with several experts on laser ultrasonics at LLNL, and to broaden his/her educational background. The PI develops a new undergraduate course in the area of mechanical behavior of materials, in which the NDE of materials will be discussed. The PI also develops NDE demonstrations for a graduate course in experimental techniques in solid mechanics. The PI serves as the faculty advisor for a professional society student group, and will host a future regional student conference at BU. The PI plans to invite representatives from local companies and educational institutions to speak to the students about the importance of NDE

Award # 0552772 Agency NSF Lead Institution Wayne State UniversityTypeExtramural

Explanatory Notes Metrology efforts support the development or improvement of methods to detect nanomaterials.

Abstract This renewal award provides support for a three-year REU Site at Wayne State University. The program builds upon the current education and research theme of the previous REU program on Smart Sensors and Integrated Devices (SSID), and also extends it to a systems approach of nano-integration with micro-systems research. The program will provide 10 students each year with research experience in cellular biophysics, biosensing science and technology, nanoscale devices, and translational applications in medicine and environmental sciences. REU participants will work closely with an interdisciplinary team of students with at least two faculty advisors to understand, develop and apply new sensor technologies starting from one or more sensing mechanisms (optical, mechanical, electrical/electromechanical, and magnetic) and extending to nano integration and biofunctionality of the sensor/biological interface.

The main objectives of the program are to provide undergraduate students with a comprehensive research experience in Nanoscale Structures and Integrated Biosensors (NSIB) and make them aware of the opportunities in graduate programs in science and engineering, or in industrial research settings. The program will place emphasis on the participation of female and underrepresented minority students, and encourage the students to pursue graduate programs in physics and engineering.

Award # 0522656 Agency NSF Lead Institution Rensselaer Polytechnic InstituteTypeExtramural

Explanatory Notes This work is aimed at developing a highly efficient chromatographic chip system able to separate nanoparticles, detect the presence of nanoparticles, and prepare samples by particle size for further chemical and biological characterization.

Abstract This project will employ microfabrication, selective filling and sol-gel nanotechnology to develop a variety of highly efficient chromatographic chip systems for bioseparations applications. Preliminary results indicate that a novel selective filling technique can be employed to create complex patterns in chromatographic chip systems. State of the art techniques employed for making sol-gel binders with unique properties will be developed for chromatographic chip systems. Efficient chromatographic chip systems will be developed by the immobilization of small particle diameter chromatographic materials using sol-gel techniques along with increased column lengths and gradient operation. The chromatographic chip systems will be evaluated for pore morphology, permeability, pore size distribution, chromatographic efficiency, and separation capability using biological test mixtures. Multifunctional systems will be examined using the selective filling sol-gel technique for integrating enzymatic digestion with gradient chromatography in a chip format. In terms of the broader impacts, this project may guide the development of a new platform technology for implementing chromatographic separations in multifunctional chip formats, which will have a potential impact on a variety of fields ranging from proteomics to environmental science. In addition, the development of selective filling sol-gel immobilization technology will facilitate advances in the state of the art of lab on chip devices. The project will also educate both undergraduate and graduate students in the state of the art of sol-gel nanotechnology as well as chip based separation systems. Chromatographic chip technology can impact areas where bioseparations are important, including environmental science and proteomics

Award # 0425780 Agency NSF Lead Institution University of PennsylvaniaTypeExtramural

Explanatory Notes This work is targeted at developing new instrumentation for detection and characterization of nanoparticles in biosystems.

Abstract The University of Pennsylvania's Nano Science and Engineering Center on Molecular Function at the Nano/Bio Interface will exploit Penn's strengths in design of molecular functionality, quantifying behavior of individual molecules, and interactions at organic/inorganic interfaces to perform research that establishes the foundation for understanding molecular function in the context of interfacing with physical systems. The NSEC unites 18 investigators from three schools (the School of Engineering and Applied Science, the School of Medicine, and the School of Arts and Sciences). Two multidisciplinary research teams are focused on aspects of the fundamental issues outlined above. Additionally, two cross cutting initiatives develop ideas integral to the research themes and make explicit links between them. The two fundamental themes are: optoelectronic function in synthetic biomolecules and mechanical motion of molecules from physiological systems. The two cross-cutting initiatives are on Molecular Nano Property Probes and Ethics in Nanotechnology.

The impact of these efforts will be felt in biophysics, bioengineering, chemistry, electrical and mechanical engineering and materials science. Discoveries from this effort will provide a sound basis for the development of new technologies for nanoscale device manufacture, drug delivery and integrated chemical sensors, enabling several near term practical applications as well provide the basis for future practical implementation. Furthermore, these issues are also at the core of understanding many complex biological/physiological processes.

The broad impact of the NSEC will occur on several levels. From a technical perspective it will articulate the critical issues that define the field at the interface of nanotechnology and biology at the molecular level. As such it will focus the attention of many disciplines to an area that is at the core of future of the field. The NSEC will impact public education, social discourse, workforce development and diversity, both locally and nationally. The implementation of educational activities in an urban environment will target a highly diverse audience at the early stage when exposure to exciting science can influence interests and future career choices, while developing models that can be implemented across the country. This NSEC will take a leadership position in the social discussion of ethics in nanoscience and technology

Award # 0084173 Agency NSF Lead Institution Florida State UniversityTypeExtramural

Explanatory Notes Metrology efforts support the development or improvement of methods to detect nanomaterials.

Abstract The National High Magnetic Field Laboratory (NHMFL) is operated by a consortium composed of the University of Florida, Florida State University, and Los Alamos National Laboratory. Florida State University administers the Laboratory as a national user facility, available competitively to users on the basis of merit. Established in 1990 and dedicated in 1994, the Laboratory through an extraordinary state-federal partnership with multi-agency participation has developed unique facilities in support of magnet-related research at the highest attainable magnetic fields. The Laboratory is structured around four major thrusts: (1) user facilities
developed in response to users' needs that are opening new frontiers for science opportunities, (2) magnet science and technology developed in partnership with the private sector to enhance U.S. competitiveness, (3) basic science research driven by a partnership between external and in-house users that drives new opportunities in high magnetic field science and technology, and (4) the integration of research and education at all levels, and partnership with academia, industry, government and international institutions to advance research and technology in the area of high magnetic fields.

Over the first ten years the NHMFL has put in place a unique range of instruments and facilities for research in high magnetic fields, including continuous field, pulsed fields, and magnetic resonance research. During this time the Laboratory has established itself as the world's leading center for multi-disciplinary research using high magnetic fields. It has developed an outstanding educational program and built strong collaborations with academic, industrial, government and international partners. The focus of the Laboratory is now shifting from a primary emphasis on magnet technology and development to include increased support for service to users from a wide range of scientific and engineering disciplines. The Laboratory is now building on the federal and state investment to realize the full scientific potential of the new facility, while the science and magnet technology programs expand the current capabilities, develop new magnet systems, and drive new science discoveries at the highest fields and at extremes of pressure and temperature. The Laboratory provides continuous fields (up to 45 tesla) in the magnetic field region formerly thought to be reserved for only pulsed magnets, and reversible pulsed fields (60 tesla for tenths of a second and up to 79 tesla for milliseconds). The availability of opportunities in magnetic resonance at 900 MHz and beyond will be a critical aspect of the Laboratory's efforts to build a users' center of excellence in very high field magnetic resonance spectroscopies. The in-house science program has been developed in cooperation with the external users and addresses a wide range of research areas including highly-correlated electron systems, magnetic materials, magnetic resonance spectroscopies applied to the chemical, physical, and biological sciences, and the development of novel instrumentation to take advantage of the magnet facilities available to users

Award # 0114372 Agency NSF Lead Institution University of Minnesota-Twin CitiesTypeExtramural

Explanatory Notes Metrology efforts support the development or improvement of methods to detect nanomaterials.

Abstract This IGERT program focuses on nanoparticle science and engineering, an inherently highly interdisciplinary field that requires researchers with a broad knowledge base of both fundamental scientific and engineering issues. The program addresses the lack of a coherent and well-organized Ph.D. training in this field. Faculty from five departments and six graduate programs at the University of Minnesota have come together to develop an interdisciplinary program transcending departmental boundaries to meet this challenge. At the core of the educational approach is the establishment of a new graduate degree program - a freestanding graduate minor program in Nanoparticle Science and Engineering. Several new interdisciplinary core courses will be developed to offer students a coherent and comprehensive set of courses. Students enrolled in the IGERT program will participate in interdisciplinary research training in research groups that include faculty and students from various departments. Nanoparticle research will be conducted in five focus areas: Two areas will address the development of enabling computational and characterization tools. These areas will form the foundation for research in application oriented areas focusing on new materials, devices, and the environment. Exceptional career development opportunities will add to the appeal of the IGERT program. These include an internship program in corporate and government laboratories, international exchange opportunities, attendance of scientific meetings at an early stage in the career, an annual interdisciplinary symposium, leadership and technology management courses, and training in ethical conduct of research. IGERT Fellows will use the excellent infrastructure at the University of Minnesota, such as its Supercomputing Institute, its Microtechnology Laboratory, and its Characterization Facility. A unique collaboration with Florida A&M University focusing on the preparation of minority undergraduate students for graduate studies and their recruitment into the IGERT program will enable building of a diverse student body.

Award # 0522005 Agency NSF Lead Institution Wayne State UniversityTypeExtramural

Explanatory Notes Efforts targeted to investigation and design of nanostructured molecular sieves using molecular and atomistic simulation for detection of toxic industrial materials at the nanoscale or molecular level.

Abstract Semi-conducting metal oxide (SMO) based sensors for the detection of chemical warfare agents (CWA) and toxic industrial materials (TIM) exhibit sensitivities on the order of parts per billion. SMO based sensors have potential advantages over other methods of chemical agent detection in terms of size, weight and cost. One limiting factor in the use of SMO based sensors for CWA/TIM detection is that these materials are non-selective. That is, there are many molecules, in addition to the agent of interest, which will yield positive detection results. The proposed work is focused on improving the selectivity of semi-conducting metal oxide sensors and the reduction of false positive responses.

Controlling the adsorption of CWA/IM onto the surfaces and their subsequent diffusion through the pores and key factors in the design of such devices. This can be done via a pre-filtering scheme, where a mixed gas stream in passed through a ceramic membrane or activated carbon. Pore size, shape and chemical composition can be tailored to selectively adsorb the molecule of interest. After being concentrated in the pre-filter, the CWA/TIM is released by a chemical displacer or a thermal pulse and sent to the SMO for detection. An alternative approach to pre-filtering is to use templating to form porous semi-conducting metal oxides with high selectivity to the target molecule. In the proposed work, molecular simulation is used to determine the absorption behavior of CWA and their simulants in the molecular sieve MCM-41.

The difficult nature of performing experiments on CWA/TIM motivates the proposed use of computational methods. Molecular simulations is well suited to the study to the toxic material and can be used to extract information on the roles specific intermolecular interactions play in the adsorption process. Because appropriate models (force fields) so not exist for the molecules of interest, significant effort is proposed on the development of transferable united-atom force fields for organophosphates, including the chemical warfare agents sarin and VX. The development of molecular models is a required first step in use of simulation for the design of SMO based sensors. These molecular models will allow for the use of simulation to investigate the effects of pore size, shape and composition on the selectivity of porous materials with respect to specific CWA/TIM. Atomistic simulations and ab initio methods are used to identify specific porous structures (shape/size) with the high selectivity necessary for the sensing of CWA/TIM with low false positives.

Broader Impacts

Recent world events, such as the release of sarin gas into the Tokyo subway system and the current concern over potential adversaries suspected development and use of chemical and biological warfare agents underscore the importance of developing highly mobile, accurate sensors and decontamination equipment for these materials. As an outcome of the proposed research, the PI expects to overcome the current limitations of the field by developing the necessary computational infrastructure for the use of simulation in the design of novel templated molecular recognition materials. These templated molecular recognition materials hold the promise of high selectivity and sensitivity to chemical warfare agents compared to other porous materials. Development of adsorbents with high affinity to a specific target molecule is expected to result I improved sensors, filters and catalytic materials. Such developments are expected to reduce the threat of the use of chemical warfare agents by terrorist organizations, improving national security and public health. Furthermore, accurate force fields describing the interactions between quest molecules and metal oxide surfaces will allow other research groups to use molecular simulation as a too to design novel adsorbent and catalytic materials for other purposes

Award # 0531171 Agency NSF Lead Institution University of Massachusetts-AmherstTypeExtramural

Explanatory Notes Metrology efforts support the development or improvement of methods to detect nanomaterials.

Abstract This Nanoscale Science and Engineering Center (NSEC) is a comprehensive research and education platform that will stimulate U.S. competitiveness by moving nanotechnology from laboratory innovation to manufacturable nanostructured components and devices. The Center for Hierarchical Manufacturing builds on recognized excellence in nanoscience and technology at UMass and a world-class program in polymer research to yield complete specification of nanostructures combining directed self-assembly and imprinting with subsequent transfer of 2-D and 3-D structures, and advanced deposition techniques, into active components, functional materials, and fully-integrated devices. Bottom-up processes will be seamlessly integrated with conventional fabrication methods for dramatic advances in semiconductor devices, microelectronics, biomedical applications, and other areas. In addition, the Center offers a new strategic model to bridge the innovation-to-implementation gap through test beds that combine leading breakthrough technology, professional market analysis, industrial-scale fabrication processes, and facilitated technology transfer.

The impact of this Center is strengthened through strong collaborators including leading R&D consultant TIAX and prototyping partner Lucent Technologies will allow the Center to drive concepts to commercialization. Students educated in this environment will be well prepared for careers that partner innovation with implementation. The Center initiates a National Nanomanufacturing Network (NNN)--a catalyst for U.S. nanomanufacturing-based economic development, a network of shared manufacturing facilities, a dynamic web-based information clearinghouse, and a pathway for university-industry-government partnerships. The NNN will integrate and amplify the impact of all NSECs and the nanomanufacturing research community. The Center will address a national need by creating and disseminating research-based multimedia instructional materials to stimulate and educate audiences ranging from K-12 students and teachers, community college learners, and the public. A strong societal implications program includes national workshops and survey studies. The Center's efforts are leveraged by strong commitments from the University of Massachusetts Amherst and the Commonwealth of Massachusetts.

Award # 0118025 Agency NSF Lead Institution Northwestern UniversityTypeExtramural

Explanatory Notes These efforts aim to develop state-of-the-art instrumentation for detection of nanoparticles with high accuracy and sensitivity.

Abstract This award establishes a Nanoscience and Engineering Center (NSEC) for Integrated Nanopatterning and Detection Technologiesat the Northwestern University. The Center will develop state-of-the-art nanopattering capabilities that are compatible with soft materials and can be used for the development of powerful new detection systems. Several emerging patterning tools and synthetic methods will be developed to fabricate nanostructured materials and devices. The Center's research strategy focuses on (1) the science and technology of surface template-driven assemblies that rely on chemical and biochemical recognition events, and (b) the experimental and theoretical study of signal transduction in soft matter nanostructures. The research program is organized under three themes: (1) Chemical and Biological recognition; (2) Nanostructured Assembly; (3) Transport and Transduction in Nanostructures Formed via Surface-Directed Assembly. As the research progresses, focus will be placed upon the development of biological (nuicleic acids and proteins) and chemical (small molecule) sensors. The research outreach will include University of Chicago, University of Illinois, Urbana-Champaign, Harold Washington University, and Argonne National Laboratory. The Center will establish formal programs with international comp[anies, universities, and laboratories in the area of nanoscale research. The Center will take a lead to establish the first global network of centers and institutes in the area of nanoscience and engineering. In the area of undergraduate education, the Center will establish Research Experience for Undergraduates (REU) and the Minority Internships in Nanotechnology (MIN) programs. The MIN program will be promoted through the minority institutions in the area. Middle and high school teachers will be provided research experience through Research Experience for Teachers (RET) program. A web-based highly flexible "Functional Nanostructure" module will be developed and distributed. New courses in nanotechnology will be developed for undergraduate and graduate levels. Industry participates in the Center activities by providing company personnel as student mentors, and by supplying source codes for software development. The Center has a program to advice on formation of startup companies.

Award # 0448835 Agency NSF Lead Institution California Institute of TechnologyTypeExtramural

Explanatory Notes This work is targeted toward understanding and developing new principles and toward the construction of versatile and inexpensive biosensors with nanoscale sensitivity.

Abstract The Pierce Lab