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A02-182 TITLE: Developing Human-Compatible Needleless Delivery Systems for Administering Bioscavengers TECHNOLOGY AREAS: Biomedical ACQUISITION PROGRAM: DSA, MRMC OBJECTIVE: The Army has a need for delivery of a bioscavenger for the protection against chemical warfare agents. The objective is to develop an alternate delivery system for introducing a bioscavenger, such as purified human serum butyrylcholinesterase (Hu BChE) into humans to afford protection against nerve agent and pesticide poisoning. In addition, the same delivery system may be used to introduce other protein/peptide/biomolecule based therapeutics in individuals. DESCRIPTION: BChE from human plasma is a drug candidate for detoxification of certain harmful chemicals to warfighters, including organophosphorus (OP) chemical warfare agents (1-4). We envisage that humans will require ~200 mg (3 mg/Kg) of Hu BChE to protect against an exposure of up to 2 LD50 of nerve agents (5, 6). While the i.v. and i.m. administration of BChE into humans is effective, it is not a highly manageable means of delivery for large volumes (~10 ml) of enzyme on the battlefield. Therefore, it is imperative to develop alternate delivery systems for the administration of protein-based prophylactics and therapeutic drugs in general, which are more practical. The military relevance for developing alternate delivery platforms is mandated in DTO CB32 (Title: Alternate delivery methods for recombinant protein vaccines) and DTO D (Title: Chemical Agent Bioscavengers). As stated in their program plans, the objectives are to evaluate respiratory vaccination and oral as well as transcutaneous delivery for recombinant vaccines and delivery of bioscavengers via gene therapy. The methods for delivering recombinant vaccines and other proteins such as bioscavengers will be slightly different due to differences in their mode of passage through different cells. We would like to explore the delivery of proteins of 300-400K molecular weight containing various amounts of carbohydrates, to the peripheral system. A pulmonary delivery system (7, 8) such as an inhaler can deliver ~200 mg of enzyme in 4-5 puffs (~30 mg each) and protect against an exposure of up to 2 LD50 of OPs for up to two weeks, and the protective levels of enzyme can be maintained by using one puff per week. Alternatively, a skin patch capable of delivering macromolecules such as protein bioscavengers could also be developed. Such patches already are in use for the delivery of small molecular weight drugs such as nicotine, scopolamine, etc., and are being developed for the delivery of peptides such as insulin and vaccines. Two other methods that can also be considered for the potential delivery of high molecular weight proteins include thermal infusion and electro infusion. This dose will also be effective in preventing long-term chronic effects due to low exposure of OPs for up to 2-3 months. The availability of an enzyme delivery system will lead to increased operational efficiency since there will be no need to carry around or wear protective clothing. This is important for soldiers in the battlefield, for marines guarding USA Embassies, and first responders that must enter an area of exposure. PHASE I: In all studies demonstrating the use of cholinesterases as bioscavengers in rodents and non-human primates, the exogenous enzyme was administered i.v., or i.m. Using these modes of delivery, >95 % of injected enzyme was found in the circulation of animals. Since needleless delivery of enzyme has never been tested, Phase I research will be restricted to delivery of exogenous BChE using any of the methods described above and examination of pharmacokinetics of BChE activity in rodents. Results will be compared with those obtained with BChE injected i.v. or i.m. into rodents. This will be the proof of concept study to see whether needleless delivery can rapidly increase plasma activity of exogenously administered enzyme. We would like to achieve the delivery of at least 75 +/-10 % enzyme activity in circulation. We will provide up to 20,000 units of purified Hu BChE for these studies. In addition, equine BChE (~65 % pure) is available from Sigma Chemical Co. PHASE II: A prototype of the delivery system will be developed and the success of the delivery system will not only be evaluated by the percent of enzyme that is delivered to the peripheral system, but also the peak level of enzyme activity, as well as the duration of enzyme at that level. This will give us an indication as to how long the system will maintain protective levels of enzyme activity. The efficacy of this enzyme as a bioscavenger will be evaluated by exposing the rodents to OPs or pesticides. If the prototype works, then we would like to obtain one system to be tested with animals exposed to live OP chemical warfare agents. If a needleless method for enzyme delivery does not result in the desired increase in plasma BChE activity, the use of additional chemicals/drugs will be investigated to increase absorption through lung capillaries (for inhaler) or skin leading to increased stability of BChE in blood. PHASE III: Produce and support a prototype of a needleless BChE delivery system during its introduction into use as a bioscavenger in the military and as a treatment for cocaine intoxication, succinylcholine-induced apnea, and pesticide overdose, for civilian use. We would like to obtain 24 systems for further testing with animals exposed to live OP chemical warfare agents. The commercialization of the system will be done with a partner in the device world. PHASE III DUAL USE APPLICATIONS: The development of a needleless delivery system such as an inhaler or skin patch for bioscavengers will likely lead to state of the art technology with respect to the delivery of protein-based prophylactic and therapeutic drugs: (A) A skin patch capable of delivering bioscavenger can be conveniently affixed to the body prior to the soldier entering the battlefield or a potentially OP contaminated area. Since the bioscavenger will be continuously delivered to the soldier, he/she will be completely protected without a need for any additional medical treatment. (B) Since inhalation is the most likely route of exposure to OPs on the battlefield, powdered or liquid inhalant-based Hu BChE can be administered on site and directly into the lung where it provides a first level of defense against inhaled OPs with no weight penalties, behavioral alterations, or performance reductions (1-4, 9). (C) The same process and advantages would exist for any first responders (civilians) reacting to terrorist nerve gas release/attack or cocaine overdose, pesticide overexposure, or succinylcholine-induced apnea (10). The needleless delivery of the bioscavenger enzyme would occur on the way to the incident and provide immediate protection without delay. (D) The inhaler/patch can also be used when increased quality of life for patients requiring chronic i.m. or i.v. administration of protein/peptide/biomolecule based therapeutics (i.e. diabetics) is needed. (E) The inhaler/patch will serve as a safer, more convenient, and more efficacious delivery system for the administration of mucosal human vaccines required for many diseases e.g., HIV. REFERENCES: 1) Doctor, B. P., Blick, D. W., Caranto, G., Castro, C.A., Gentry, M. K., Maxwell, D. M., Murphy, M. R., Schutz, M., Waibel, K., and Wolfe, A. D. Cholinesterases as scavengers for organophosphorus compounds: Protection of primate performance against soman toxicity. Chem. Biol. Interact., 87, 285-293, 1993. 2) Maxwell, D. M., Castro, C. A., De La Hoz, D. M., Gentry, M. K., Gold, M. B., Solana, R. P., Wolfe, A. D., and Doctor, B. P. Protection of rhesus monkeys against soman and prevention of performance decrement by pretreatment with acetylcholinesterase. Toxicol. Appl. Pharmacol., 115, 44-49, 1992. 3) Wolfe, A. D., Blick, D. W., Murphy, M. R., Miller, S. A., Gentry, M. K., Hartgraves, S. L., and Doctor, B. P. Use of cholinesterases as pretreatment drugs for the protection of rhesus monkeys against soman toxicity. Toxicol. Appl. Pharmacol., 117, 189-193, 1992. 4) Raveh, L., Grauer, E., Grunwald, J., Cohen, E., and Ashani, Y. The stoichiometry of protection against soman and VX toxicity in monkeys pretreated with human butyrylcholinesterase. Toxicol. Appl. Pharmacol., 145, 43-53, 1997. 5) Ashani, Y., Grauer, E., Grunwald, J., Allon, N., Raveh, L. Current capabilities in extrapolating from animal to human the capacity of human butyrylcholinesterase to detoxify organophosphates in Structure and Function of Cholinesterases and Related Proteins (Doctor, B. P., Taylor, P., Quinn, D. M., Rotundo, R. L. and Gentry, M. K., eds) pp255-260, Plenum Press, New York., 1998. 6) Doctor, B. P., Maxwell, D. M., Ashani, Y., Saxena, A., and Gordon, R. K. New approaches to medical protection against chemical warfare nerve agents in Chemical Warfare Agents: Toxicity at low levels (Somani, S. M. and Romano, J. A., Jr., eds) pp 191-214, CRC Press, New York, 2001. 7) Patton, J. Breathing life into protein drugs. Nat Biotechnol. 16, 141-143, 1998. 8) Byron, P. R., and Patton, J. S. Drug delivery via the respiratory tract. J. Aerosol. Med. 7, 49-75, 1994. 9) Matzke, S. M., Oubre, J. L., Caranto, G. R., Gentry, M. K., and Galbicka, G. Behavioral and immunological effects of exogenous butyrylcholinesterase in rhesus monkeys. Pharmacol Biochem Behav. 62, 523-30, 1999.
Ashani, Y. Prospective of human butyrylcholinesterase as a detoxifying antidote and potential regulator of controlled-release drugs. Drug Dev. Res. 50, 298-308, 2000. KEYWORDS: bioscavengers, human, butyrylcholinesterase, pulmonary delivery, inhaler, organophosphorus chemical warfare agents, pesticides, cocaine. A02-183 TITLE: Rapid Serological Diagnosis of Scrub Typhus Infections TECHNOLOGY AREAS: Biomedical ACQUISITION PROGRAM: DSA, MRMC OBJECTIVE: Adapt state-of-the-art technology to develop a field-usable assay capable of diagnosing scrub typhus infection in ill patients. REQUIREMENT: To quickly and accurately assess febrile patients for infection with Orientia tsutsugamushi, the causative agent of scrub typhus. This disease poses a threat to U.S. forces deployed to the Asian/Australian/Pacific theater during contingency and peacekeeping operations. Development of an FDA-approved assay for the detection of O. tsutsugamushi is therefore a high priority for the DoD. DESIRED CAPABILITY/CONCEPT OF THE FINAL PRODUCT: We envision a rapid detection assay capable of determining whether an ill patient is infected with Orientia tsutsugamushi, the causative agent of scrub typhus. The assay should detect: 1) IgM and IgG antibodies specific for Orientia tsutsugamushi, OR 2) O. tsutsugamushi-specific antigen, OR 3) an alternative marker that is specific for O. tsutsugamushi. The assay must be rapid (<45 min), one- or two-step format, and stable (storage at 35 degrees C for 2 years). The assay should be as sensitive and specific as the r56 recombinant-antigen scrub typhus enzyme-linked immunosorbent assay (ELISA). The assay must be soldier-friendly (i.e., easy to operate), inexpensive, portable, use heat-stable reagents, and have no special storage requirements. DESCRIPTION: The ability to quickly identify infectious agents causing disease in military troops is a major component of the Military Infectious Disease Research Program (MIDRP). Scrub typhus, caused by Orientia tsutsugamushi, is a major military threat throughout much of the Asian/Pacific region, to include Afghanistan/Pakistan. Mortality in untreated cases can exceed 30%. Initiation of treatment (tetracycline group antibiotics) in a timely manner can reduce mortality rates due to scrub typhus to close to 0%; however, initiation of treatment is often delayed due to difficulties in the diagnosis of scrub typhus. A principle technical barrier to the accurate diagnosis of scrub typhus is the lack of FDA-approved devices for detecting Orientia tsutsugamushi-specific antibody or antigen that are: 1) one step, 2) field-usable, 3) utilize stable reagents, and 4) have no special storage or equipment requirements. The indirect immunofluorescent antibody (IFA) assay and the indirect immunoperoxidase (IIP) test are the most widely used tests for the diagnosis of scrub typhus. Unfortunately, neither of these tests are FDA approved. In addition, each test is time-consuming, requires highly trained personnel, relies on locally produced antigen preparations, and is subjective. Therefore, neither the IFA nor the IIP tests meet the needs of the U.S. Department of Defense, nor can either assay be considered a “gold-standard” against which to evaluate the efficacy of candidate assays. Although alternative assays for the detection of O. tsutsugamushi are commercially available, only one of these assays is currently FDA approved. This whole cell assay requires specialized equipment, refrigeration of reagents, and highly trained personnel. However, scrub typhus typically threatens U.S. troops deployed to developing countries where access to such facilities and equipment is unavailable. The principle requirements of a field-usable scrub typhus assay are that it should be inexpensive, simple to perform, accurate, be produced according to GMP standards, be registered with the FDA, use heat-stable reagents, and have no special storage needs. PHASE I: Determine the feasibility of the concept by developing a prototype diagnostic assay that has the potential to meet the broad needs discussed in this topic. Coordinate with the COR for access to required reagents, test sera and/or specimens from the Naval Medical Research Institute (NMRI) or the Armed Forces Research Institute of Medical Sciences (AFRIMS). Reagents, test sera and/or specimens will be provided at no cost to the SBIR contract. PHASE II: Provide up to 3 initial lots of 250 prototype assays/lot to the COR -- these initial lots will be evaluated at NMRI/AFRIMS for sensitivity/specificity and feedback provided to the company by the COR. Feedback regarding the sensitivity/specificity of each lot of prototype assays will be used to optimize each subsequent lot of assays. The goal in Phase II is the development of a prototype assay that provides 95% sensitivity and specificity when compared to the ELISA. Once requirements have been met, provide a final lot of 500 prototype assays for confirmation of sensitivity/specificity. Testing for sensitivity/specificity by NMRI/AFRIMS will be conducted at no cost to the SBIR contract. PHASE III: Provide a final lot of 5,000 assays to the COR for comprehensive field-testing to ensure that all requirements have been met. Data from field-testing will be used for submission for FDA registration. Field testing will be conducted at no cost to the SBIR contract. DUAL USE APPLICATIONS: The developed technology could be used by military forces operating in Asia and the Pacific region and by government or commercial medical centers in the developing countries in this region to accurately and rapidly identify soldiers or civilians infected with scrub typhus. COMMERCIAL APPLICAITONS (SPIN-OFF): Government or commercial medical centers in the developing countries in this region of the world require cheap, easy-to-use diagnostic assays for the detection of scrub typhus. The development of the proposed device would provide an urgently needed device that would be commercially viable. COMMERCIAL APPLICATIONS (SPIN-ON): Development of a technology that meets the military requirement for a device to diagnose scrub typhus could allow for the subsequent development of similar devices for the detection of other diseases of public health and military concern (i.e., leptospirosis or dengue). TECHNICAL RISK: There is a degree of technical risk involved in this project. Currently existing scrub typhus diagnostic assays do not meet the requirements outlined in this proposal -- the candidate contractor is expected to use innovation and in-house expertise to develop a prototype that meets the needs of the Department of Defense. ACCESS TO GOVERNMENT FACILITIES AND SUPPLIES: T he development of the required diagnostic assay will require support (test sera and reagents, access to specimens, etc.) from the Armed Forces Research Institute of Medical Sciences in Bangkok, Thailand and/or the Naval Medical Research Institute in Silver Spring, Maryland. The candidate contractor should coordinate with the COR for any required support prior to the submission of the proposal. REFERENCES: 1) Pradutkanchana J, Silpapojakul K, Paxton H, Pradutkanchana S, Kelly DJ, Strickman D, 1997. Comparative evaluation of four serodiagnostic tests for scrub typhus in Thailand. Trans R Soc Trop Med Hyg 91: 425-428. 2) Kovacova E, Kazar J, 2000. Rickettsial diseases and their serological diagnosis. Clin Lab 46: 239-245. 3) Kostman J R, 1996. Laboratory diagnosis of rickettsial diseases. Clin Dermatol 14: 301-306. 4) Suwanabun N, Chouriyagune C, Eamsila C, Watcharapichat P, Dasch G A, Howard R S, Kelly D J, 1997. Evaluation of an enzyme-linked immunosorbent assay in Thai scrub typhus patients. Am J Trop Med Hyg 56: 38-43. 5) Land M V, Ching W M, Dasch G A, Zhang Z, Kelly D J, Graves S R, Devine P L, 2000. Evaluation of a commercially available recombinant-protein enzyme-linked immunosorbent assay for detection of antibodies produced in scrub typhus rickettsial infections. J Clin Microbiol 38: 2701-2705. 6) Ching W M, Rowland D, Zhang Z, Bourgeois A L, Kelly D, Dasch G A, Devine P L, 2001. Early Diagnosis of Scrub Typhus with a Rapid Flow Assay Using Recombinant Major Outer Membrane Protein Antigen (r56) of Orientia tsutsugamushi. Clin Diagn Lab Immunol 8: 409-414.
2. Simulator should enable the control of acute hemorrhage from wounds above and below the knee and elbow joints. 3. Simulator should demonstrate the effects of appropriate physical pressure applied to pulsating arterial flow. 4. Simulator should demonstrate the use of tourniquets on differing morphological types. 5. Simulator should enable the teaching of the correct application of a tourniquet, by both medical and non-medical personnel to include self-application, using a range of tourniquets including improvised devices. 6. Simulator should be low-cost and rugged enough to be made available in considerable numbers for first-responder combat casualty care throughout the military. 7. Though it might be useful to combine the teaching of this skill with other medical skills it is not essential and should not be attempted if the result is increased complexity and cost, which will limit the numbers available for training.
1) Operational Capability Elements: Joint Medical Readiness,” p. 6 (section 3.2.1), Joint Science and Technology Plan for Telemedicine (submitted to and approved by the DDR&E, 1 Oct 97). 2) Leitch R A. The Three Block War: Medical Implications of Urban Conflict. US Medicine. February 2001. 3) Pueschel, M. Antietam Provides Lessons in Care. US Medicine. September 2001. KEYWORDS: Modeling, simulation, combat casualty care skills training, exsanguinating hemorrhage, tourniquet. A02-185 TITLE: In-situ Aquatic Biomonitoring Platform TECHNOLOGY AREAS: Materials/Processes, Biomedical ACQUISITION PROGRAM: DSA, MRMC OBJECTIVE: The objective is to develop an aquatic biomonitoring platform that integrates biological and chemical sensors to provide continuous, real time monitoring for developing toxic conditions in bodies of water that may serve as sources for drinking water (e.g., streams, rivers, lakes). The platform will assess the possible impairment of military forces that may consume or contact the water during training or deployment. DESCRIPTION: The U.S. Army Center for Environmental Health Research (USACEHR), in conducting research in the field of deployment toxicology, is developing new methods for real-time assessment of continuously monitored biological endpoints to define the toxicity of water. Biological endpoints incorporated in the aquatic biomonitoring platform include responses from living cells, tissues, or whole organisms. Continuous monitoring of biological responses can be used for early warning of developing toxic hazards that may be due to unsuspected materials or the joint action of chemical mixtures. We are seeking development of an autonomous platform that can be deployed directly in aquatic systems (streams, rivers, lakes, reservoirs) to house both biological monitors and chemical sensors. Examples of technologies that could be included in the platform include a fish ventilatory monitor (Shedd et al., 2001), a clam monitor (Waller et al., 1996) and multi-probe water quality monitors (pH, dissolved oxygen, temperature, conductivity) made by several manufacturers. Most biomonitoring systems are designed for streamside or fixed facility deployment, and there are no presently available systems that are deployable in-stream and integrate multiple chemical and biological endpoints. Such integration presents significant technical challenges. We are seeking innovative and creative research approaches to address the aquatic platform requirements described below: 1. Capable of deployment in a variety of aquatic systems of varying depth and current, including streams, rivers, lakes and reservoirs. 2. Self-powered, capable of meeting the electrical requirements of biological and chemical monitors (e.g., see examples mentioned above). 3. Includes data acquisition, analysis, and output capabilities for both biological and chemical monitors. 4. Flexible architecture to permit expansion to include additional chemical or biological sensors. 5. Communication capabilities to permit remote data access and two-way communication with sensor systems. 6. Designed to resist vandalism and to be as inconspicuous as possible. 7. Portable and rugged, with minimal size and weight to meet above requirements. PHASE I: Design and construct a prototype aquatic platform. Proof of concept will be accomplished through testing under laboratory conditions. Experimentation must show that the platform exhibits requirements 1 through 5 listed above. At a minimum, the platform must integrate at least one existing biological monitor (as described above) and one existing multi-parameter chemical sensor complementary to the biological monitor and be capable of submerged, unattended operation (including data transmission and reception) without external power. PHASE II: Refine and field-test the aquatic platform in both lakes and rivers. Integrate at least one biological monitoring system and one multi-probe chemical monitor (dissolved oxygen, conductivity, temperature, pH). Address requirements 1 through 7, listed above. Demonstrate that real-time, continuous data from the platform can be provided in a format suitable for off-platform transmission and remote analysis and that control of on-board functions can be achieved through remote access. PHASE III DUAL-USE APPLICATION: The field-deployable platform will be integrated with other similar platforms creating a network to provide early warning of developing toxic conditions in water and their potential hazard 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 substantially reducing false positives and by improving identification of 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. USACEHR would consider providing non-SBIR funding after successful completion of Phase II. Single aquatic platforms have commercial application for the early detection of toxic chemical spills. The use of a network of aquatic platforms has broad civilian application, especially given EPA's current emphasis on watershed-based monitoring and regulation. OPERATING AND SUPPORT COST REDUCTION (OSCR): Biomonitoring systems are most often used in fixed facilities near bodies of water to be monitored. New technology is needed to permit field deployment of a range of biological and chemical sensors in a platform that is portable, easily deployable, and better capable of supporting decision-making under field conditions associated with military operations. The alternative to real-time toxicity monitoring is the collection and preservation of environmental samples, followed by transportation to a remote laboratory for testing, a procedure which is vastly more costly and time consuming and which is not useful for rapid decision making. REFERENCES: 1) Kramer, K. J., Botterweg, J. 1991. Aquatic biological early warning systems: and overview. In: Jeffrey, D. J., Madden, B., editors. Bioindicators and Environmental Management. London, UK: Academic Press. pp. 95-126. 2) Shedd, T. R., van der Schalie, W. H., Widder, M. W., Burton, D. T., Burrows E.P. 2001. Long-term operation of an automated fish biomonitoring system for continuous effluent acute toxicity surveillance. Bull. Environ. Contam. Toxicol. 66(3):392-398. 3 )van der Schalie, W. H., T. R. Shedd, P. L. Knechtges, and M. W. Widder. 2001. Using higher organisms in biological early warning systems for real-time toxicity detection. Biosensors & Bioelectronics 16: 457-465. 4) Waller W T, Acevedo M F, Allen HJ, Schwalm F U. 1996. The Use of Remotely Sensed Bioelectric Action Potentials to Evaluate Episodic Toxicity Events and Ambient Toxicity. College Station, TX: Texas Water Resources Institute, Texas A&M University. 172 pp. KEYWORDS: in situ biomonitoring, aquatic toxicity, real-time monitoring, biomonitoring platform Directory: osbp -> SBIR -> solicitations solicitations -> Army sbir 09. 1 Proposal submission instructions dod small Business Innovation (sbir) Program solicitations -> Navy sbir fy09. 1 Proposal submission instructions solicitations -> Army 16. 3 Small Business Innovation Research (sbir) Proposal Submission Instructions solicitations -> Air force 12. 1 Small Business Innovation Research (sbir) Proposal Submission Instructions solicitations -> Army 14. 1 Small Business Innovation Research (sbir) Proposal Submission Instructions solicitations -> Navy small business innovation research program submitting Proposals on Navy Topics solicitations -> Navy small business innovation research program solicitations -> Armament research, development and engineering center solicitations -> Army 17. 1 Small Business Innovation Research (sbir) Proposal Submission Instructions solicitations -> Navy 11. 3 Small Business Innovation Research (sbir) Proposal Submission Instructions Download 1.78 Mb. 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