Submission of proposals
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| OBJECTIVE: Develop a sensor / tool to measure body hydration status (via measuring muscle water content) in soldiers during deployment and training. Skeletal muscle water content will decrease when soldiers dehydrate and this measurement will serve as an important component of a body hydration monitoring system. Currently there is no valid quantitative measure of body hydration status for field use (rapid, technically simple & not easily confounded).
Soldiers will commonly dehydrate (by 2% to 5% of body weight) due to high rates of water loss from environmental exposure and performing stressful physical work. Dehydration by modest amounts (2% of body weight) will decrease cognitive and physical work capabilities (even in temperate environments), and larger water deficits can have devastating effects performance and soldier health. Likewise, over-hydration can cause serious health problems (hyponatremia) and many of its symptoms mimic dehydration. The goal of this topic is to develop a tool to measure skeletal muscle water content changes in soldiers during field operations. Soldiers will wear the muscle water sensor (and another sensor) to provide a body hydration monitoring system. Such a tool will have civilian medical use to assess hydration status of various patient populations. The employed technology must be safe and eventually be lightweight and compact with low-power requirements. DESCRIPTION: The envisioned device would employ a technology that is non-invasive or minimally invasive and can measure muscle water content. System requirements include: (1) accuracy of 2% within a range from 2% to 40% reductions in muscle water, (2) not be confounded by plasma and skeletal muscle electrolyte disturbances; (3) not be confounded by skeletal muscle contractions; (4) not interfere with physiologic function, and (5) user friendly technology with potential to be used in field operations. PHASE I: The contractor will demonstrate proof-of-concept of the approach to measure skeletal muscle water content and potential to discriminate small (2%) reductions in muscle water. This will be supported by documentation of basis for approach, prototype system specifications and data regarding scientific validity. PHASE II: Contractor will build 5 working prototypes and supporting hardware/software interfaces for evaluations in laboratory in animal and human models. This will be supported by overall system design document and hardware / software prototype. Animal or human studies will be required to obtain appropriate Department of Army, Institutional Review Board approvals, this may take 6-9 months. PHASE III: This sensor / tool will be integrated with at least one other sensor to develop a commercial body hydration monitor system. The analytic instrument will be extensively tested in laboratory / field studies to demonstrate a sensitive, specific and reliable system for military application. This instrument will be used to manage deployed soldier hydration status to maximize performance and reduce risk of environmental injuries. Such a tool will have civilian medical use to assess hydration status of various institutionalized patient, athlete and worker populations. References: Body Fluid Balance in Exercise and Sport. E.R. Buskirk and S.M. Puhl, Eds., Boca Raton, FL: CRC Press, 1996. Mack, G. W. and E.R. Nadel. Body Fluid Balance during Heat Stress in Humans. In: Handbook of Physiology, Section 4: Environmental Physiology. C.M. Blatteis and M.J. Fregley, Eds., New York: Oxford University Press for the American Physiological Society, Chapter 10, 187-214, 1996. Montain, S.J., M.N. Sawka, and C.B. Wenger. Hyponatremia Associated with Exercise: Risk Factors and Pathogenesis. Exercise and Sports Science Reviews. 29:113-117, 2001. O’Brien, C., A.J. Young and M.N. Sawka. Bioelectrical Impedance to Estimate Changes in Hydration Status. International Journal of Sports Medicine. 23:361-366, 2002. Sawka, M.N. and E. F. Coyle. Influence of Body Water and Blood Volume on Thermoregulation and Exercise - Heat Performance. Exercise and Sport Sciences Reviews. 27:167-218, 1999. Sawka, M.M. and S. J. Montain. Fluid and Electrolyte Balance: Effects on Thermoregulation and Exercise in Heat. Present Knowledge in Nutrition. B.A. Bowman and R.M. Russell, Eds., Washington, DC, ILSI Life Sciences, Chapter 11, 15-126, 2001. KEYWORDS: dehydration, body water, hydration, hypohydration, skeletal muscle water, water balance A03-157 TITLE: Generic Flavivirus-Based Vaccine Platform for Biological Threat Agents TECHNOLOGY AREAS: Biomedical ACQUISITION PROGRAM: DSA, MRMC OBJECTIVE: To develop a generic vaccine platform based on defective flavivirus-like particles(FLP's) that can be used to deliver protective antigens of heterologous pathogens. DESCRIPTION: Live virus vaccines have been the most successful strategy in producing immunity to viral diseases. Among the flaviviruses, for example yellow fever, dengue, Japanese encephalitis, natural infection induces long-term, probably life-long immunity. The live-attenuated 17D yellow fever vaccine have been given to millions with excellent safety record and induces high protection efficacy (>95%) through a single dose vaccination. The disadvantages of live-virus vaccines are its high reactogenicity and potential risk of reversion to virulent wild-type virus. Defective flavivirus-like particles containing almost all of its 10 coding genes including structural and non-structural loci, may offer the advantages of strong immunogenicity and safety feature of not reverting to wild-type virus. Results from the work of Kunjin virus suggest that development of a noninfectious vaccine delivery system based on encapsidation of a noncytopathic flavivirus replicon expressing heterologous genes is feasible. (1) Sub-genomic virus-like particles of dengue viruse has been constructed. (2) Recently subgenomic replicons of another flavivirus, West Nile, was shown to be capbale of delivering heterologous protein expression in hamster kidney cells. (3) Unlike naked DNA vaccines or adenovirus-based vectors flaviviruses do not cause persistent infections and do not have any oncogenic potential. Such flavivirus FLP’s may be useful as vectors to deliver protective antigens from other pathogens. PHASE I: This phase will be to determine feasibility. The goals will be: a. To develop cell lines that can stably express subgenomic viral construct containing all non-structural dengue or yellow fever 17D viral coding regions (without protein E region); b. To develop a rescue (or helper) virus vector containing the dengue or yellow fever virus structural gene, protein E that will produce defective FLP’s. by infecting the transfectant cell line harboring dengue or Yellow fever non-structural sequences; c. To develop rescue virus vector containing the dengue protein E structural gene and other heterologous genes of interest that can be used to produce defective FLP's expressing the other antigens of interest. The lab-grade yield of FLP's will need to be at least 10exp6 FLP's/ml. PHASE II: This phase will be to develop: a. process of scale up production of FLP's (pre-GMP) of at least 10exp6 FLP's/ml; b. process of concentration of FLP's should the yield be low. PHASE III: Pre-clinical safety and animal testing and submission of IND. Manufacture pilot lot of test article under Good Manufacturing Conditions for human clinical trials (Technology Readiness Level 5). The development of high titers FLP's preparation can be used as a potential vaccine candidate to provide efficient protection for US military personnels that are deployed to Flavivirus endemic areas. The future plan after Phase III for the FLP's product will be safety and immunogenicity testing of the dengue VLP to be co-sponsored by commercial company and U.S. Army (Technology Readiness Level 6). The success of FLP's commercialization from this topic will provide an efficient means of developing new vaccine candidates against the emerging militarilly relevalent infectious pathogens. REFERENCES: 1) Khromykh A. A., Varnavski A. N. and Westaway E. G. Encapsidation of the flavivirus kunjin replicon RNA by using a complementation system providing Kunjin virus structural proteins in trans. J Virol 1998 Jul;72(7):5967-77. 2) Pang X., Zhang M., Dayton A. I. Development of dengue virus replicons expressing HIV-1 gp120 and other heterologous genes: a potential future tool for dual vaccination against dengue virus and HIV. BMC Microbiol 2001;1(1):28. 3) Shi P-Y, Tilgner M. and Lo M. K. Construction and characterization of subgenomic replicons of New York strain of West Nile Virus. Virology 2002;296:219-233. KEYWORDS: pre-GMP, feasibility A03-158 TITLE: Enhanced Detection and High-Throughput Screening of Proteomic Signatures/biomarkers in Neoplastic Tissue TECHNOLOGY AREAS: Biomedical ACQUISITION PROGRAM: DSA, MRMC OBJECTIVE: To design and implement a proteomics-based assay system that will incorporate sensitive quantitative detection of biomarkers with high-throughput capabilities. DESCRIPTION: The advent of functional genomics has provided new avenues for the identification of genes that initiate and support tumor growth. This new technology coupled with analysis of the proteome can lead to new and improved methods of diagnosis as well as therapy that is tailored to a tumor’s particular genomic and proteomic profile. Microarray analysis offers a sensitive technique to measure levels of gene transcription allowing one to identify differences in m-RNA production between normal and neoplastic tissue. While microarrays provide valuable information in this regard, gene products regulated at the level of translation and/or post-translational modification are missing from this data profile. Analyses of the proteome, especially the enzymatic proteome, which measure alterations in activity would add additional important information to this picture. The field of proteomics is in its infancy and current technologies for analysis are limited to measuring abundance without considering protein activity. Therefore, it is of great importance to develop this technology further with both of these objectives in mind. Information from both microarray analysis and proteomic analysis will lead to early and accurate diagnosis of cancer as well as increase our ability to adapt to a tumor’s changing phenotype as a particular therapy progresses. Additionally, this technology will be very useful in generating infectious disease profiles and profiles arising out of exposure to agents commonly used in bio- and chemical warfare, all of which have high military relevance. The overall goal of this solicitation is to develop a high-throughput diagnostic tool using protein activity profiles to identify specific disease states such as cancer. PHASE I: Propose a family of proteins to focus efforts on and design a strategy for synthesis of a probe for detection and measurement of specific protein activity that is associated with breast, ovarian, prostate, and/or lung cancer. PHASE II: Initiate probe synthesis and characterization in a suitable assay system. Begin analyses of proteomes derived from normal and pathological tissue samples. The probe should be able to successfully distinguish between normal and cancerous/diseased tissue using well characterized controls where possible. Proteomic profiles should correlate with clinical and pathological findings. PHASE III: This phase would focus on design of high-throughput platforms for the activity assay with the goal to develop a rapid diagnostic tool that can analyze multiple tissue samples accurately. This tool will be highly applicable to military relevant topics including force protection. Early detection of cancers and/or infectious diseases is needed to best care for military personnel and DOD beneficiaries, and to reduce the health care costs incurred in treating and caring for these individuals. Direct application of this technology to military settings is for rapid and accurate detection of exposure to infectious diseases and biological and chemical agents in the environment. Infectious diseases outbreaks, either through terrorism or natural worldwide outbreaks, must be detected and tracked in order to deal with managing the initial response, targeting resources, evaluating effectiveness, and managing the ongoing response. A proteomic profile assay system will enhance the ability to detect specific diseases and also enhance the time required to identify outbreak. REFERENCES: 1. Haab B.B., Dunham M.J., and Brown P.O. Protein microarrays for highly parallel detection and quantitation of specific proteins and antibodies in complex solutions. Genome Biology. 2001. 2:4.1-4.13. 2. Jessani N., Liu Y., Humphrey M., and Cravatt B.F. Enzyme activity profiles of the secreted and membrane proteome that depict cancer cell invasiveness. Proceedings of the National Academy of Sciences. 2002. 99:10335-10340. 3. Veenendaal L.M., Jin H., Ran S., Cheung L., Navone N., Marks J.W., Waltenberger J., Thorpe P., and Rosenblum M.G. In vitro and in vivo studies of a VEGF121/rGelonin chimeric fusion toxin targeting the neovasculature of solid tumors. Proceedings of the National Academy of Sciences. 2002. 99:7866-7871. 4. Zhang H-T, Kacharmina J.E., Miyashiro K., Greene M.I., and Eberwine J. Protein quantification from complex protein mixtures using a proteomics methodology with single-cell resolution. Proceedings of the National Academy of Sciences. 2001. 98:5497-5502.
A03-159 TITLE: Personal Area Network for Warfighter Physiological Status Monitoring (WPSM) TECHNOLOGY AREAS: Biomedical ACQUISITION PROGRAM: dsa,mrmc OBJECTIVE: Develop and demonstrate a wearable personal area network (PAN) to support routine, continuous ambulatory physiological status monitoring of physically active warfighters. DESCRIPTION: Physiological monitoring of soldiers during training and combat operations is needed to reduce the likelihood of casualties and to improve remote casualty management. To achieve this goal, a reliable personal area network (PAN) (~2 meter range; minimum 9600 baud) is needed to interconnect intelligent sensors scattered about the body (chest, wrist, boot, head, canteen) and one or more data fusion points where physiological state classification can occur. The challenge is to develop a low-power, compact, lightweight PAN that has a minimal electromagnetic signature, and can function in a changeable, constrained, and harsh environment. The system must be easy to don and doff, and accommodate variations in physique, clothing and body-worn equipment, and sensor placement. The number and type of networked sensors will vary with mission. Data streams may be unsynchronized, noisy, and have missing data, and sensors may fail. The PAN must tolerate extremes of temperature, vibration, and immersion. This degree of adaptability suggests a wired/wireless or wireless design. We seek a novel PAN design that can: (a) interface in a plug-and-play fashion with at least four sensors or sensor-node channels, (b) data transfer and the control of a variety of physiological sensors such as electrocardiogram (ECG), respiration rate, and skin temperature, each with distinctly different data rates and information content, (c) correlate and time synchronize multiple heterogeneous signals and events in time, (d) reconfigure with changes in the sensor array, including adapting to non-responsive and faulty sensors without undue perturbation to available bandwidth and network latency, (e) provide reliable, predictable, low-latency delivery of time series data to a central processor (a key to later processing of the data collected and delivered via the PAN), and (f) can accommodate an unlimited number of PAN users given a maximum spatial density (proximity) of one system per square meter. Comparing and contrasting chosen physical and link layer (software protocol) approaches with evolving industry standards for short-range low-power systems such as IEEE 802.15 (http://grouper.ieee.org/groups/802/15) is desirable. PHASE I: Define an overall PAN architecture concept, identify planned use of commercial as well as custom elements, and provide detailed performance predictions for the primary performance metrics which are achievable bandwidth, concurrent channels, energy use, and susceptibility to standoff detection and jamming. Phase I may also include risk reduction efforts such as development and demonstration of a single channel solution using commercial available parts and measurement of primary performance metrics. PHASE II: Develop at least 10 prototype PAN systems suitable for field trials and performance measurement. The emphasis will be on the sensor interface and data collection and collation elements of the PAN, with an interface to a commercial body-worn computer. The Phase II effort will include field trials of the PAN under various working and training conditions to determine the reliability, detectability, jam-ability, energy utilization, bit error rate test performance, and tolerance to the failure of individual sensors. The result of the Phase II effort will be a comprehensive characterization of PAN performance, and a plan for ruggedization and packaging of the PAN elements to support operational deployment. PHASE III DUAL USE APPLICATIONS: The offeror should aggressively pursue civilian PAN applications. The advancements in telemedicine technology and Web-based monitoring of home health patients drive needs to remotely and automatically evaluate the clinical condition of patients. These sensing and data collection requirements are typically a subset of the capabilities desired for warfighter physiological status monitoring. A robust military PAN technology would also be useful in real-time monitoring of health status of firefighters and emergency personnel working in harsh environments. REFERENCES: 1. http://www.usariem.army.mil/wpsm/index.html2 2. Hoyt, R.W., J. Reifman, T.S. Coster, and M.J. Buller. Combat medical informatics: present and future. In: Biomedical Informatics: One Discipline. In: Bio*medical Informatics: One Discipline. Isaac S. Kohane, MD, PhD, ed., Proceedings of the 2002 AMIA Annual Symposium ISBN: 1-5603-600-4.
A03-160 TITLE: Biomonitors for Real-Time Air Toxicity Monitoring TECHNOLOGY AREAS: Biomedical ACQUISITION PROGRAM: DSA, MRMC OBJECTIVE: The objective is to develop and integrate advanced biomonitoring technology into a field-deployable platform to provide continuous, real-time monitoring for developing toxic conditions in air. The platform will identify potential health effects on deployed forces resulting from exposures to a wide array of airborne toxic chemicals. DESCRIPTION: The U.S. Army Center for Environmental Health Research (USACEHR), in conducting research in the field of deployment toxicology, seeks new methods for real-time assessment of continuously monitored biological endpoints to define airborne toxicity. Biological endpoints are considered to include responses from living cells, tissues, or whole organisms. Although many chemical or biochemical sensors are being developed to detect exposure to individual toxic materials, this effort focuses on using real-time biological responses to identify a broad range of toxic hazards that may be due to unsuspected materials or the joint action of chemical mixtures. Technologies are sought for incorporation into a sensor platform deployed in the environment to provide continuous, real-time monitoring information. We are seeking innovative and creative research approaches to address the air toxicity monitoring requirements described below. It is anticipated that more than one biomonitoring approach may be required to achieve these goals: 1. Use biomonitoring technology, including cell- or tissue-based biomonitors or multicellular organism biomonitors, to provide a sensitive and rapid response to a broad range of airborne toxicants (with varying modes of toxic action). 2. Minimize interference caused by variations in environmental parameters such as temperature, airborne particulates, humidity, etc., while continuously monitoring representative air samples. 3. Minimize sample preparation requirements while maintaining air sample integrity. 4. Ensure that living biomonitor components can survive transport and can be stored for at least 30 days prior to use. 5. Provide for continuous, real-time data acquisition and analyses. 6. Integrate functions in a field-deployable platform. PHASE I: Conduct research to demonstrate the efficacy of one or more individual biomonitors (incorporating responses from living cells, tissues, or whole organisms) for continuous, real-time toxicity detection. The biomonitor(s) will be original or will represent significant extensions, applications, or improvements over published methods. Experimentation must show that the biomonitor(s) exhibit the above characteristics. Proof of concept will be accomplished during a continuous, two-week monitoring period by demonstrating biomonitor response within 30 minutes to at least one toxic chemical of relevance to the military with minimal “false alarms” (responses in the absence of toxic chemicals). PHASE II: Expand Phase I research to demonstrate the biomonitor=s capability to accurately and continuously monitor developing toxic conditions in real time with minimal interference from variations in environmental conditions. Integrate the biomonitor(s) into a field-deployable platform. Include specific sensors for chemicals or environmental parameters, as required, to augment the biomonitor(s). Provide real-time, continuous data from the platform in a format suitable for real-time off-platform transmission and remote analysis. Evaluate the sensitivity and response characteristics of the biomonitor(s) through laboratory tests with various classes of chemicals including, but not limited to, pesticides, organic solvents, and military-unique substances. Provide a field test of the system that demonstrates operation under ambient air conditions and shows that biological components meet transportation and storage requirements. PHASE III DUAL-USE APPLICATION: Integrate the field-deployable platform with other similar platforms, creating a network to provide early warning of developing toxic conditions in air and potential hazards to troops. A variety of field applications are possible, including assessment of environmental hazards to troops pre-, during, and post-deployment. Field tests will apply platform/network under variable environmental conditions. The new platforms will increase the reliability and usefulness of current biomonitoring technology by identifying potential toxic chemical hazards to troops. Also, the platforms may be used to monitor and assess the environmental impacts of military site activities and the compliance of such activities with regulatory requirements. Given current on-going concerns regarding accidental or intentional release of air toxics, this technology will have broad application for both state and local governments. USACEHR would consider providing non-SBIR funding after successful completion of Phase II. OPERATING AND SUPPORT COST REDUCTION (OSCR): Current air monitoring approaches cannot detect a full range of developing toxic conditions as quickly as needed for decision-making under field conditions associated with military operations. Present field monitoring devices have focused on specific threat agents, but it is increasingly recognized that a wide range of toxic industrial chemicals (TICs) and materials (TIMs) may pose hazards to troops. This effort will complement chemical detection systems by providing real-time indications of developing toxic hazards due to unsuspected materials or chemical mixtures, thus providing an important capability that is not presently available. REFERENCES: 1) Bromenshank, J. J., Smith, G. C., Watson, V. J. 1995. Assessing ecological risks in terrestrial systems with honey bees. In: Butterworth, F. M. et al., editors. Biomonitors and Biomarkers as Indicators of Environmental Change. New York: Plenum Press. pp. 9-30. 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