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Santa Barbara, CA, United States

Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 151.63K | Year: 2013

DESCRIPTION (provided by applicant): The goals of this project are twofold: a) to develop a new technique for nanoscale Mass spectrometry imaging based on AFM based tip enhanced IR ablation (nanoIR-MS). b) to apply this technique towards the application ofSingle cell imaging. Information on the chemical composition within a cell has implications in the understanding of cell metabolism, division, disease states, ecological effects etc. Given current technology limitations, most current analyses of biological systems are performed on groups of cells with the assumption that an ensemble average from the group will yield a useful result. However, this typically is not a valid assumption as cells of the same type exhibit diverse metabolic makeup depending on their phase in the cycle, history and interaction with the environment. Thus it is important that cells be analyzed individually in order to detect rare cells (e.g. circulating tumor cells), transient cell states, the influence of the cell environment on cells and states and aid in the understanding of differences in gene expression, protein levels, and small- molecule distributions at the single cell level. Cell heterogeneity is particularly significant in the -omis fields such as genomics, proteomics, lipidomics, and metabolomics that characterize biological systems at a molecular level. This significance led to the NIH launching a special focus program on Single cell Analysis Tools in late 2011. The size of mammalian cells is on the order of 10 m and therefore the imaging of single cells requires imaging spatial resolution of at least 1 m. The nanoIR-MS technology has a potential spatial resolution of at least 10x better than this or 100 nm which offers the possibility of the imaging of biomolecules in organelles. But to achieve an innovative and commercially successful product from this proposal, 1 m spatial resolution would suffice. One of the Specific Aims of this proposal is to demonstrate that the nanoIR-MS technique can be applied for Single Cell Imaging. We will demonstrate this on two types of Single cells: Cells from Mouse brain and also to identify single Circulating Tumor cells (CTCs). As reiterated in our Letter of Support from our collaborator, Prof. Yeh who is an Oncology research surgeon, CTCs are the fundamental entities primarily responsible for spawning metastatic disease and there is a current lack of characterization technologies to identify them . To cure epithelial-based cancers-such as cancers of the breast, prostate, lung, colon andpancreas-therapies need to be directed towards those cells that cause metastases. However, the majority of metastatic lesions are never biopsied due to anatomic inaccessibility or associated morbidity of the procedure. CTCs offer a readily accessible means of studying the biology of metastatic cells throughout the course of disease and are often referred to as 'Liquid Biopsy'. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: The goals of this project are twofold: a) to develop a new technique for nanoscale Mass spectrometry imaging based on AFM based tip enhanced IR ablation (nanoIR-MS). b) To apply this technique towards the application of Single cell imaging. We will demonstrate the application of this platform technology on single mouse braincells and to identify single cells of Circulatory Tumor cells.


Grant
Agency: Department of Energy | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 150.00K | Year: 2014

AFM-based infrared spectroscopy (AFM-IR) pioneered by Dazzi et al provides ~100X improvement in spatial resolution over conventional infrared microspectroscopy, enabling chemical analysis at the nanoscale. It has already been successfully applied to many applications, including polymer composites and films, photonic devices, organic photovoltaics, fuel cell membranes, and bacteria for biofuels applications and other energy applications. One of the key disadvantages of current AFM-IR instruments is that they require expensive tunable infrared laser sources, with prices ranging from $100-$300K. This high source cost drives the AFM-IR system cost to $350-$500K, exceeding the budget range of most researchers who could benefit from its capabilities. Anasys Instruments proposes to develop a new low cost mid-IR source to enable a low cost and high performance AFM-IR instrument, operable over the full mid-IR wavelength range. We will target a source price of & lt;$10K, more than 10-30X less expensive than conventional IR sources for nanoscale spectroscopy. To achieve this goal, we will (1) leverage previous technical achievements that enable the use of low intensity IR sources; and (2) develop new technology to modulate the intensity of the IR source at frequencies that provide efficient detection by the AFM. Commercial Applications and Other Benefits: The proposed instrument will provide low cost chemical analysis at the nanoscale. Specifically, it will provide: (1) ~100X improved spatial resolution compared to convention infrared microspectroscopy; (2) & gt;2X lower cost than current AFM-IR spectroscopy that will double the addressable market; (3)AFM-IR to DOE and other synchrotron light sources for ~50X higher spatial resolution synchrotron infrared microspectroscopy. By dramatically reducing the cost of infrared nanospectroscopy (currently affordable only to multi-billion dollar companies and top-tier universities), this project will make a powerful new analytical technique much more widely available, thus accelerating science and industry in energy, advanced materials, life sciences and many other areas.


Grant
Agency: Department of Energy | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.00M | Year: 2015

Infrared spectroscopy is the most widely used technique for chemical characterization with a worldwide market of over $1B annually, but has fundamental spatial resolution limits of at the scale of many microns. Atomic Force Microscope based infrared spectroscopy (AFM-IR) has recently broken this spatial resolution limit using the tip of an AFM to detect IR absorption with spatial resolution >100X better than conventional IR instruments. AFM-IR has already been successfully applied to many applications, including polymer composites and films, photonic devices, organic photovoltaics, fuel cell membranes, and bacteria for biofuels applications and other energy applications. Unfortunately, the high instrument cost, driven by expensive tunable IR lasers (~$150K), has dramatically constrained the adoption of the AFM-IR technique to top tier universities/national labs and very large companies. While demand is increasing for high resolution infrared spectroscopy at DOE and other synchrotron IR beamlines, there has not been a viable technical approach to interface AFM-IR to these synchrotron sources. As such there is a tremendous opportunity to expand the impact of infrared nanospectroscopy if: (1) the AFM-IR technique can be enabled with a much lower cost IR source; and (2) made accessible to synchrotron beamlines. Proposal Approach: Following successful Phase I research, the proposer will develop a new low cost mid-IR source to enable a low cost/high performance AFM-IR instrument, covering the full mid-IR wavelength range. The new platform will employ a low cost thermal source in combination with a novel proprietary technology that enables it use for AFM-IR. This effort will leverage previous investments by DOE that resulted in the development of resonance enhanced AFM-IR that enables detection of IR absorption from nanoscale regions of a sample with improved sensitivity. The Phase I research has demonstrated feasibility of key aspects the proposed system, including the feasibility of the low cost mid-IR source and associated spectroscopic measurements. Phase II efforts will (1) optimize and extend IR modulation techniques developed in Phase I; (2) demonstrate resonance enhanced AFM-IR spectroscopy with the low cost thermal source; (3) build a production prototype instrument suitable for customer sample measurements; and (4) demonstrate low cost infrared nanospectroscopy on real world samples. This project will also interface AFM-IR and s-SNOM capabilities to the synchrotron at the DOE Advanced Light Source. Commercial Applications and Other Benefits: The proposed instrument will provide broadly applicable chemical analysis at the nanoscale on an affordable platform. Specifically, it will provide: (1) ~100X improved spatial resolution compared to convention instruments; (2) lower cost than current AFM-IR instruments; and (3) a platform to interface AFM-IR and s-SNOM capabilities to DOE and other synchrotrons. By dramatically reducing the cost of infrared nanospectroscopy (currently affordable only to multi-billion dollar companies and top-tier universities), this project will make a powerful new analytical technique much more widely and will accelerate R&D in diverse fields including polymers, energy, photonics, life sciences, pharmaceuticals and others.


Grant
Agency: Department of Energy | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.00M | Year: 2015

Mass Spectrometry (MS) is one of the most widely used analytical techniques for chemical characterization. It is used routinely in a wide variety of industrial and academic laboratories in a wide set of applications such as polymers, pharmaceutics, life sciences, photovoltaics etc. Despite MS being a very powerful chemical analysis technique, when used as the detection system in chemical imaging its spatial resolution is restricted to several tens of microns when used with conventional atmospheric pressure surface sampling methods. On the other hand, Atomic Force Microscopy (AFM) is a powerful technique that can be used for nanoscale morphological and physical property measurements but one of its greatest drawbacks is that it has been chemically blind. Our proposal will bridge this divide by implementing and commercializing the combination of AFM with the definitive elemental and molecular characterization capabilities of MS. Our technical approach is to use an AFM thermal probe to desorb nanoscale sample areas which are then collected, ionized and delivered to a MS Inlet. The feasibility of our technical approach for nanoscale chemical imaging was demonstrated during Phase I where 500nm resolution was shown for real world polymer samples. A wide range of scientifically relevant compound classes were thermally desorbed by applying heat to an AFM probe and subsequent mass spectrometric chemical detection. Chemical images of patterned dye printouts, bacteria, mouse brain tissue and phase separated polymer thin films were obtained. A pre-commercial beta version of the AFM-MS product will be developed in Phase II in collaboration with sub-contractor, Dr. Gary Van Berkel, ORNL Distinguished Scientist and Group Leader of ORNLs Organic Mass Spectrometry Group. The goal will be to enable routine multi-modal, nanoscale chemical imaging of real-world samples provided from a number of private and academic research entities. Desorption, transport and ionization of sample material will be further optimized and new designs will implemented for high sample throughput. Commercial Applications and Other Benefits: By utilizing nanoscale MS chemical information, we will target specific applications that will have the most commercial impact such as surface blooming of stabilization additives in polymer manufacturing, discovery of better drug delivery and contaminate free packaging materials and the study of biological functions through the analysis of metabolites in tissues and cells. However, we anticipate significant downstream benefits in broad areas of materials, pharmaceutical, and life sciences application areas including but not limited to the development of advanced pharmaceutics, polymer materials, nano-contaminate detection in semiconductors and electronics, organic photovoltaic materials, automotive materials, materials for energy generation/storage, cell biology, and cancer research.


Grant
Agency: Department of Energy | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.00M | Year: 2015

Infrared spectroscopy is the most widely used technique for chemical characterization with a worldwide market of over $1B annually, but has fundamental spatial resolution limits at the scale of many microns. Anasys pioneered the field of Atomic Force Microscope based infrared spectroscopy (AFM-IR) which recently broke this spatial resolution limit using the tip of an AFM to detect IR absorption with spatial resolution >100X better than conventional IR instruments. The research and development efforts that have occurred during the Phase I and Phase II projects have demonstrated the capability of a new technique called Resonant Enhanced AFM-IR with sensitivity more than 100X better than current commercial AFM-IR capabilities, allowing chemical analysis down to the monolayer level. In addition, we have demonstrated the ability to perform Resonance Enhanced AFM-IR measurements in liquid opening a range of new applications. Unfortunately the Resonance Enhanced AFM-IR technique has two key limitations which this proposal seeks to solve: 1) Operation in liquid is still not of sufficient sensitivity for many research applications 2) The Resonance Enhanced AFM-IR measurement is not fast enough for substantial commercial adoption. Proposal Approach: We will use a combination of new cantilever designs; new detection techniques and algorithmic and electronics improvements to achieve our goals. Our sub-contractor in this proposal is our longtime collaborator Prof Mikhail Belkin of UT-Austin who is a co-inventor with Anasys of the Resonance Enhanced AFM-IR approach and an expert in the field. Commercial Applications and Other Benefits: It will enable the AFM-IR technique to penetrate the large and important Life Sciences field where it is required that samples are hydrated. The speed improvements will make it a powerful new analytical technique that will be adopted much more widely and will accelerate R&D in diverse fields including polymers, energy, photonics, life sciences, pharmaceuticals and others.

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