Defense health program (dhp) 16. C small Business Technology Transfer (sttr) Program Proposal Submission Instructions
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DHP STTR 16.C Topic Descriptions
TECHNOLOGY AREA(S): Biomedical OBJECTIVE: Traditional dose-response models depend on monotonic data and often fail when applied to non-monotonic data. Assessment of dose response should be an integral part of establishing the safety and efficacy of any drug. The objective of this topic is to develop a novel approach applicable to general pharmacologic, toxicological, or other biomedical data, that exhibit a non-monotonic dose-response relationship for which traditional parametric models fail. Software will be developed to analyze dose-response relationships using both monotonic and non-monotonic data. DESCRIPTION: Identifying dose response, and developing dose-response models, is essential in determining safe and hazardous levels and dosages for drugs, potential pollutants, and other substances to which humans or other organisms are exposed. Drug efficiency is primarily determined by the drug-target binding affinity. In pharmacodynamics projects, the drug-target affinity is usually assessed by comparing dose-response curves; the stronger the drug binds to the target, the steeper the curve. One of the critical indices of the dose-response curve, the half-maximal inhibitory concentration (IC50), is commonly used to compare the binding affinities of drugs to the same target. The IC50 represents the concentration of a drug that is required for 50% of maximal inhibition in vitro. To estimate the IC50 value, parametric logistic models (PLMs) are well accepted. The advantages of a parametric logistic model are that (a) it is symmetrical about the IC50; (b) it is monotonic; and (c) parameters such as IC50 can be easily estimated under certain conditions. But these advantages become restrictive when some conditions fail. Recent researches on human immunodeficiency virus mutants developing resistance to antiviral drugs show that the dose-response curve may not always be monotonic (Zhang et al. 2013). If a PLM is used to fit data when the dose-response pattern is non-monotonic, the fit is poor, and the estimated IC50 and other parameters are not reliable, and may even be misleading. Finding appropriate estimation of IC50 and other parameters for this type of dose-response relationship poses statistical challenges, and several parametric and nonparametric methods have been proposed in the statistical literature. For example, Ramsay [1988] studied the use of monotone splines to model a dose-response function. Hall and Heckman [2000] proposed an alternative approach that focuses on “running gradient” estimation over very short intervals. To appropriately estimate the pattern of observations and then estimate IC50, Zhang et al. (2013) developed a robust modeling strategy to test whether (a) the model fitting is comparable to a PLM when the observed data are monotonic, and (b) the model fitting yields reasonable estimates when the data pattern is non-monotonic and a PLM would not work. Military agencies, government agencies and private sponsors would all benefit from new and improved approaches to reasoned exploratory data analysis in analyzing and describing dose-response data. PHASE I: Since the real dose-response relationship is often non-monotonic and traditional monotonic model fitting leads to results that either do not converge or are biased, a new and novel approach is needed. Zhang et al. (2013) used robust modeling with local linear regression to fit a large survey dataset and showed the nonparametric model is better suited than traditional monotonic models to fit this J-shaped curve; this model might be extended to other shape curves. A potential limitation of the proposed method is its performance with a moderate sample size. In Phase I, the following tests should be completed: 1. Perform and summarize the current dose-response model by monotonic and non-monotonic approach and perform and symmetrize monotonicity testing. 2. Verify and modify the Zhang et al. approach and other non-linear approaches. 3. Perform a simulation study to compare the selected model and monotonic modeling for a variety of sample sizes. 4. Select the best approaches including classic dose-response models and the proposed model, and design an algorithm which answers at a minimum, the following questions: a. Is there any drug effect? b. What is the maximum tolerated dose? c. What is the nature of the dose-response relationship? d. Is IC50 optimal to measure the relationship? e. Does a nonlinear dose-response model work? f. If so, does its IC50 concur with that obtained using the Zhang et al. method? 5. Develop the work plan for Phase II PHASE II: In Phase II, the selected contractor should use both actual data and simulation data to verify and modify the following: 1. When the dose-response relationship and associated parameters such as IC50 are studied, the proposed approach is robust and efficient, verified and modified by the following conditions: if the monotonicity assumption is satisfied, the results based on the proposed method closes to those based on traditional sigmoidal model fitting; if monotonicity is not satisfied, the approach can realistically estimate the parameters, such as IC50. 2. Using this newly developed approach, important dose-response features will not be omitted. 3. The proposed method can also be used for other dose-response modeling scenarios, such as hormesis dose-response curves used in toxicology. 4. The approach can also be used to estimate the half-maximal effective concentration, which is commonly used when the drug enhances its target's activity, and the lethal dose 50%, or the lethal concentration or time of a toxic substance or radiation representing the dose needed to kill half the tested population. Then the selected contractor will develop computer software for implementing the proposed statistical methods and make it available for public use. The software should have the following features: 5. A variety of model-based approaches to dose-response assuming a functional relationship between the response and the dose following a pre-specified parametric model. 6. A variety of fitted models used to test if a dose-response relationship is present, and estimate other parameters of interest. 7. Modeling the dose-response relationship generally requires additional assumptions as opposed to using multiple comparison procedures, but can provide additional information - the software can examine these assumptions and handle missing data. 8. A variety of models may be used to characterize a dose-response relationship: linear, quadratic, orthogonal polynomials, exponential, linear in log-dose, and non-parametric. 9. The software can help users select the suitable model according the data, and will be made available to the scientific community. During this phase, the performance of the software will be evaluated in a variety of studies to conclusively demonstrate that it meets the requirements of this topic. By the conclusion of Phase II, the selected contractor will have completed the development of the software. The contractor will provide a report that summarizes the performance of the software to the Walter Reed Army Institute of Research. PHASE III DUAL USE APPLICATIONS: In Phase III, the STTR performer's software will be available for military and civilian use. We envision that the team that develops the software will market it for Government laboratory use, and negotiate commercial licensing with commercial and academic markets. As an alternative, any or all of these artifacts might be released into the open source community through organizations such as the Open Source Electronic Health Record Alliance (OSEHRA) or Open Health IT Tools or similar organizations for open sources licensing. Based on negotiations with the types of government and commercial organizations cited, it is possible that hybrid commercial and open source licensing could occur. In the case where these artifacts are released into the open source community, the STTR awardee would need to develop and provide a plan to state how it would sell additional consulting, software implementation and/or training services around their workflow model, technical implementation guidelines, and/or software controls. REFERENCES: 1. Ramsay J (1988) Monotone regression splines in action. Statistical Science 3: 425–441 2. Bowman A, Jones M, Gijbels I (1998) Testing monotonicity of regression. Journal of Computational and Graphical Statistics 7: 489–500 3. Hall, P. and Heckman, N. E. (2000). Testing for monotonicity of a regression mean by calibrating for linear functions, Annals of Statistics 28: 20-39. 4. Zhang, H., Holden-Wiltse, J., Wang, J. and Liang, H. (2013). A strategy to model nonmonotonic dose-response curve and estimate IC50, PLOS ONE 8: 1-7 (e69301). KEYWORDS: Dose-Response, Maximal Inhibitory, Non-Monotonic, Parametric Logistic Model, Robust Parametric Logistic Model, Safety Dosage,
TECHNOLOGY AREA(S): Biomedical OBJECTIVE: Develop a miniaturized, orthogonal (i.e. multi-modal) sensor system to detect and quantify exhaled volatile organic compounds (VOCs) in austere operational environments. This system will be used to establish and monitor the frequency, magnitude, and chemical make-up of exhaled VOCs to detect the generation of specific VOC profiles associated with maladaptive physiological responses, alert the operator and supervisor(s) to injury prior to performance decrement, and correlate exposure parameters to injury onset for potential mitigation prior to warfighter compromise. The developed system must be real-time, able to be integrated into all current flight masks and regulators, conform to industry standard safety guidelines with respect to use in enriched oxygen atmospheres in hypobaric and hyperbaric conditions, include ability for volatile library expansion, uploading and display of disease specific VOC algorithms, maintain a log of acquired data, and be capable of logistically maintainable use between missions. DESCRIPTION: High concentrations of supplemental oxygen are used routinely by pilots and divers prior to and during missions to prevent and treat decompression sickness, avoid detection during covert operations, and to support oxygenation following pulmonary injury. Oxygen use is limited however, by the onset of pulmonary oxygen toxicity (PO2T) which can significantly damage pulmonary tissues leading to decreased performance among other adverse effects. PO2T is traditionally diagnosed after the fact by symptomatology and chest X-ray. Current policy focuses on preventing PO2T in an operational environment by adhering to exposure limits that were developed based on empirical evidence of PO2T. Multi day diving with a ppO2 of 1.3 ATA is limited to 4 h per day for 16 h per week (1). However, the effectiveness of these limits can vary greatly among individuals; without an individualized test for PO2T, these exposure limits can unduly restrict operational duration, delay return to duty, and significantly impact mission readiness. A VOC based breath test for PO2T would provide a novel, sensitive, objective, and direct measure of PO2T for pilots, divers, and patients, improving oxygen exposure limits in all populations. Breath analysis of VOCs is a non-invasive technique that has a high probability of predicting and monitoring the onset of pulmonary injury due to a wide variety of environmental and infectious exposures (2). Currently breath samples are absorbed into a tube containing a binding matrix and transported to the lab to be desorbed and analyzed. Gas chromatography-mass spectrometry (GC-MS) and absorption spectrometry are used to measure VOCs from these samples to create a VOC profile. To date, more than 3,000 VOCs have been detected in exhaled breath, 1% of which are likely to contain disease-specific VOCs, such as alkanes, isoprenes, benzenes and methyl alkanes. VOCs have successfully detected disease states including lung cancer (3) and pulmonary tuberculosis, and are actively researched for monitoring pulmonary oxygen toxicity, acute hypoxia, radiation exposure, heart transplant rejection, viral influenza, and breast cancer. This VOC based technology may also support other operational scenarios that are associated with pulmonary injury to include: high altitude operations, noxious substance inhalation, exposures to natural or weaponized biologic agents, and exposure to radioactive substances. While GC-MS is the gold standard method to detect and quantify VOCs from exhaled breath, this technology in its conventional form is unsuitable for real-time monitoring in austere operational environments. This topic seeks to address this gap in capability by developing a ruggedized VOC detection device that can bring VOC detection capabilities for disease detection and mitigation to the warfighter or medical provider operating in austere environments. PHASE I: VOCs are constantly produced in the body and are derived from diverse metabolic processes. Successful analysis of these compounds in exhaled breath will require the ability to detect, identify, and quantify thousands of organic and inorganic species simultaneously. Operational utilization of this detector suite will also require a focus on minimization of space, weight, and power requirements for integration into aircraft and diver masks. Successful completion of Phase I will require development of a sensor suite with the ability to detect, identify and quantify the inorganic components of breathing mixes, (i.e., nitrogen, oxygen, carbon dioxide, argon, helium, and water vapor), as well as individual detectable VOCs within the exhaled breath in real-time. The detector should be able to identify and quantify the complete complement of compounds in the NIST 14 Mass Spectral Library (v.2.0, 2016) (4). The Phase I prototype will not require completion of the sample collection, signal processing, and display modules, but will be expected to demonstrate separation and detection of the EPA method TO-15 VOC compound list (reference 5, Table 1) at low levels (<50 parts-per-billion) in a laboratory setting with sensitivity and specificity as described in the TO-15 method. The prototype should be no more than 2kg and 1.0 cubic foot in size. PHASE II: Phase II will focus on end-to-end implementation of the sampling, sensing, and electronics necessary for real-time VOC detection in a form factor designed for integration into masks and regulators while compensating for environmental changes such as pressure, temperature, vibration, and humidity. The prototype should have a volume of no more than 0.5ft3 and a mass of <1.0kg, and ideally a volume of <0.25ft3 and a mass of <0.5kg. This sensor should not require consumable reagents such as carrier gasses, disposable columns etc. but have a mechanism to control sample concentration to the detector to avoid saturation. The developed sensor package will require battery power and be ruggedized to withstand requirements for three operational scenarios: Flight use (i.e., high G, variable pressure, high vibration environment, <1.0kg), Dive use (i.e., hyperbaric pressure, highly enriched oxygen atmospheres, water immersion, <1.0kg) and Field use (i.e., dirt/sand/debris infiltration, extreme temperature exposure (-20oC-100oC), sun exposure, light weight <1.0kg). The signal processing algorithm utilized on the sensor platform prototype should contain an extensible library of compounds. Additionally, the platform prototype should have novel design consideration for sufficient flexibility to allow for future expansion of selective sensors. Laboratory based characterization and validation of the integrated sensor package and electronics for a minimum of 1 operational scenario (dive, flight, or field) will be required for successful completion of Phase II. PHASE III DUAL USE APPLICATIONS: Follow-on government and civilian activities are expected to be pursued by the offeror, i.e. in civilian diving and aerospace applications. Commercial benefits include a revolutionary capability for noninvasive assessment of physiological status in a variety of austere settings. Additionally, to expand the use of the device to medical diagnosis FDA medical device certification will be pursued. Potential military customer targets include: Naval Sea Systems Command (NAVSEA), Naval Air Systems Command, Marine Corps Forces Special Operations Command (MARSOC), as well as OCONUS and CONUS military treatment facilities. Potential sponsors/advanced developers for this technology includes: Defense Health Program (DHP), Navy Advanced Medical Development (AMD), United States Army Medical Materiel Development Activity (USAMMDA), and United States Army Medical Materiel Agency (USAMMA). REFERENCES: 1. US NAVY Dive manual: http://www.supsalv.org/pdf/Dive%20Manual%20Rev%206%20with%20Chg%20A.pdf 2. Schnabel R, Fijten R, Smolinska A, Dallinga J, Boumans ML, Stobberingh E, Boots A, Roekaerts P, Bergmans D, van Schooten FJ. Analysis of volatile organic compounds in exhaled breath to diagnose ventilator-associated pneumonia. Sci Rep. 2015 Nov 26;5:17179. doi: 10.1038/srep17179. PMID: 26608483 3. Krilaviciute A, Heiss JA, Leja M, Kupcinskas J, Haick H, Brenner H. Detection of cancer through exhaled breath: a systematic review. Oncotarget. 2015 Nov 17;6(36):38643-57. doi: 10.18632/oncotarget.5938. Review.PMID: 26440312 4. NIST 11 Mass Spectral Library (v.2.0, 2011). http://www.nist.gov/srd/nist1a.cfm 5. EPA method TO-15, Table 1. https://www3.epa.gov/ttnamti1/files/ambient/airtox/to-15r.pdf KEYWORDS: Volatile Organic Compound, Breath Exhalate, Pulmonary Injury, Oxygen, Physiologic Monitor, Real-time Sensor, extreme environments
TECHNOLOGY AREA(S): Biomedical OBJECTIVE: Ongoing studies at WRAIR are focused on characterizing the rodent response to traumatic stressors in order to screen and identify novel therapeutic candidate compounds for clinical development to treat post-traumatic stress disorder (PTSD), a condition that may negatively affect the psychological health of the warfighter. This topic aims to develop an automated scoring program for identification and classification of rodent ultrasonic vocalizations. Automated scoring of these vocalizations will improve the depth of ongoing preclinical studies and may contribute to identification of a novel therapeutic candidate compound that supports the warfighter. DESCRIPTION: The ongoing preclinical screening process at WRAIR is developing the capability to use ultrasonic vocalizations (USVs) to understand the effects of traumatic stress in rats, and screen for candidate compounds that may reduce aversive responding to trauma or reminder cues of trauma. The goal of this basic research is to identify a novel preclinical candidate compound for eventual development to improve warfighter psychological health. USVs are classifiable and are generated in multiple well-characterized scenarios, making them a useful add-on to behavioral studies. USVs are difficult to detect and localize, and cannot be heard by predators in the air or on the ground when the vocalizations are emitted in underground burrows (1). Another source of interference is background environmental noise (i.e., wind, rain). This is an issue of note when detecting USVs in the experimental environment that has a myriad of background noise that can interfere with accurate analysis by a detection system (i.e., white noise, electrical noise). From birth, rats emit early ‘isolation calls’ (at ~40kHz); Around 21 days of age, pup isolation calls change and the juvenile rat begins to emit the two primary USVs emitted by adult rats: the 22kHz alarm call and the 50kHz nonaggressive call (1). 22kHz calls represent an adaptive defense mechanism, and are emitted in potentially aversive or threatening situations. These 22kHz alarm calls may have a frequency range of ~18-32kHz, although are generally in a narrow bandwidth of 20-23kHz, and have a long duration of ~300-4000ms, with very little frequency modulation. 50kHz calls are characterized as appetitive, nonaggressive, ‘friendly’, or neutral calls and generally appear to be related to a positive emotion or social situation. These calls have a frequency range of ~32-96kHz and have a significantly shorter duration of ~30-50ms, with more frequency modulation. Two major types of 50kHz calls have been classified: constant frequency (flat) calls and frequency modulated (step calls with trills) calls. At least 14 call categories have been reported for 50-kHz USVs: complex, upward ramp, downward ramp, flat, short, split, step up, step down, multi-step, trill, flat-trill combination, trill with jumps, inverted U, and composite (2). USVs emitted by mice are also distinct between pups and adults. Mouse pups emit USVs (above 35kHz). Adult mouse USVs (~30 to 110kHz) are emitted exclusively during non-aversive behaviors or non-aggressive interactions, and are generally thought to function to facilitate or inhibit social interactions (3). Mouse USVs are defined by syllable type, which occurs when a unit of sound is separated by a silent period before another sound begins. Syllable types include: frequency-modulated downsweep, u-shaped modulated frequencies, frequency-modulated upsweep, constant frequencies, and hump shaped modulated frequencies). Computerized electronic equipment is required to transform the frequency of USVs and lower the frequency into the human hearing range. Parameters are used to characterize these vocalizations and include the duration (in ms), bandwidth (in kHz), frequency modulation, and the overall sonographic pattern of the call (e.g., sweep, trill, step). Output of these programs use a spectrogram to represent the information about call frequency (i.e., maximum frequency, peak frequency, minimum frequency, bandwidth) and length. As many vocalizations are made in a series, other variables can include call rate, number of calls in a series, number of series, inter-series time intervals. There are existing programs to detect and score USVs. However, these programs each have limitations which fail to meet the required automated detection and scoring criteria for this effort. A newly developed automated detection and scoring program needs to work in a range of experimental environments. It is also important to be able to parse out these vocalizations that occur in conjunction with background noise to identify the relevant vocalizations and screen traumatic responses in the preclinical model of traumatic stress. PHASE I: Develop, demonstrate, and deliver a prototype automated program that, given a pre-recorded file, will score rat and mouse ultrasonic vocalizations (USVs). Rodents USVs are emitted in a variety of forms and types (for rats: i.e., fixed frequency calls, frequency modulated calls, and trills; for mice: syllable type). A key requirement for the software is to accurately detect and classify sonographic information from the recorded file such as the type of call (frequency and duration based) and the total number of calls, but also parameters such as starting and ending frequencies, frequency with peak energy, frequency modulation, and duration of calls. Required Phase I deliverable will include a demonstration of a proof of concept automated program with the ability to score and define rat (40kHz pup isolation vocalizations, 22kHz vocalizations, 50kHz vocalizations) and mouse (pup versus adult, syllable type) ultrasonic vocalizations from a pre-recorded file. Commercially available hardware and recording program will be used to record the USVs. Pre-recorded rodent USVs collected at WRAIR will be made available the awardee for use in proof of concept automated program demonstrations. The deliverable will perform an analysis of USV recordings with output to show that the program is sufficient to score USVs. The program output needs to be verified by hand scoring of sample recordings, which is the current method the laboratory uses to score vocalizations. PHASE II: Using results from Phase I, Phase II work will refine, finalize, and validate the automated scoring program for rodent ultrasonic vocalizations. Commercially available hardware and recording program will be used to record the USVs; the recorded USV files from this hardware will be used to develop the fully operational final program. Required of the Phase II deliverable is a fully operational final program which accurately performs automated scoring of rat (40kHz pup isolation vocalizations, 22kHz vocalizations, 50kHz vocalizations) and mouse (pup versus adult, syllable type) ultrasonic vocalizations. The product will also classify different types of rat 50kHz vocalizations which occur with frequency modulation (i.e., constant frequency/flat calls and frequency modulated calls/step calls with trills) and various types of mouse pup isolation or cold calls and adult mouse syllable types (frequency-modulated downsweep, u-shaped modulated frequencies, frequency-modulated upsweep, constant frequencies, and hump shaped modulated frequencies). PHASE III DUAL USE APPLICATIONS: The algorithms and program developed under this topic will be relevant to all rodent ultrasonic vocalizations- this effort will deliver a product that is broadly usable both by DoD and industry. Although there are programs in the current market place for ultrasonic detection and scoring, these products lack total reliability for detection and scoring of all vocalizations and classification type. In addition to the relevant need for military research, as developed in Phase I and II, this program may be marketed to academic and industrial research laboratories as a complete vocalizations detection package. In addition to rodent USVs, there is potential for the proprietors to generate add-on algorithms for detection and scoring of other animals which communicate in ultrasonic methods (bats, birds, whales, dolphins, frogs, insects), and can be used both in the laboratory and in the natural environment. Potential DoD customers include basic research enterprises such as WRAIR. REFERENCES: 1. Brudzynski, S.M. (2009). Communication of adult rats by ultrasonic vocalizations: biological, socialbiological, and neuroscience applications. ILAR, 50, 43-50. PMID: 19106451; http://ilarjournal.oxfordjournals.org/content/50/1/43.full.pdf+html 2. Wright, J.M., Gourdon, J.C., Clarke, P.B. (2010). Identification of multiple call categories within the rich repertoire of adult rat 50-kHz ultrasonic vocalizations: effects of amphetamine and social context. Psychopharmacol, 211, 1-13. PMID: 20443111; http://link.springer.com/article/10.1007%2Fs 3. Portfors, C.V. (2007). Types and functions of ultrasonic vocalizations in laboratory rats and mice. JAALAS, 46, 28-34. PMID: 17203913; http://neuro-s.co.jp/images/product/1-30/TypesandFunctionsofUSVinLabRatsandMice.pdf 4. Reno, J.M., Marker, B., Cormack, L.K., Schallert, T., Duvauchelle, C.L. (2013). Automating ultrasonic vocalization analyses: the WAAVES program. J Neurosci Methods, 219, 155-161. PMID: 23832016; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931607/ KEYWORDS: Rodent (Rat, Mouse), Ultrasonic vocalizations (USV), Acoustic, Communication (Aversive, Social, Pup), Spectrogram, Recording, Automated Scoring, Program
TECHNOLOGY AREA(S): Biomedical OBJECTIVE: Develop an integrated system for field, clinic and laboratory preparation of biological specimens for microscopy and histopathology that meets the current needs for (1) Safety, (2) High quality samples, and (3) Easy handling. DESCRIPTION: Quality and consistent preparation of biological specimens for microscopy and histopathology is required to make accurate diagnoses in general hospitals, field hospitals, and to assess natural and bio-warfare disease threats. Consistent preparation with safety and easy handling of the range of biological specimens is difficult to achieve even in the best laboratory conditions, and becomes more difficult in remote locations, and when pathogenic specimens must be prepared in level 3 or 4 biological safety laboratory (BSL) bio-containment facilities. The Pathology Division from USAMRIID seeks an integrated system for field, clinic and laboratory preparation of biological specimens that can address the following specific needs and improve the current sample preparation procedures. (1) Safety: All biological specimens are required to be immersed in toxic fixatives such as 4% formaldehyde, or 2% glutaraldehyde to preserve antigenicity or morphology. The handling and preparation of these specimens thus can expose personnel to infectious agents and to toxic reagents. We are looking for a prototype of a capsule-like specimen container that has pre-loaded fixative. When the specimen is collected and the capsule cap is closed, it will allow the immediate release of the fixative to mix with the samples thereby eliminating the direct handling of the toxic reagent. (2) High quality of samples: There are multiple steps involved when personnel collect and fix specimen with fixatives. Achieving rapid initial chemical fixation is challenging and any delays in initial fixation reduce sample quality. We are looking for a prototype of a capsule-like specimen container that contained pre-loaded fixative and will be able to mix the fixative with the specimen in seconds in order to ensure high quality preservation. (3) Easy handling: Specimens handling can also cause specimen contamination and cross-contamination that can be especially problematic for molecular diagnostics. Intensive training and high expectation for personnel is typically required. We are looking for a prototype of an easy-to-learn system that will simplify the training procedure and make sample preparation easy and consistent for all the personnel. We envision simple operations such as handling Eppendorf tubes and simple pipetting will be efficient enough to accomplish the tasks. The proposed system and apparatus should improve personnel safety by reducing the handling of infectious materials and toxic preparative reagents. The proposed system and apparatus should improve quality, reliability, and traceability and be efficient with respect to the amount of specimen required, reagents used, and personnel effort. It should reduce specimen contamination and cross-contamination, be efficient and effective when handling individual and multiple specimens, and be capable of handling a wide range of specimen types. The system should also be easily used by minimally trained personnel in the field, and by personnel operating in bio-containment laboratories. PHASE I: During the Phase I award, the contrast recipient will design, develop and demonstrate the concept of a prototype system for preparing microscopy specimens that is expected to improve processing safety, quality and efficiency. The concept will be developed for a capsule-like specimen container that will be pre-loaded with fixative as a Field Fixation Unit (FFU). This will include the design of the concept, establishing performance goals, identification of key elements, design and materials specification for manufacturing, analysis of anticipated performance, and the development of at least one functional prototype. PHASE II: During the Phase II award, the contract recipient will build on Phase I work to produce working prototypes for multiple tissue types and microscopy (or histology) applications. This will include reagent kits for multiple microscopy and histology applications. Since specimen orientation is also useful in microscopy and histology, it would be desirable if the system can enable sample orientation. Prototypes will be tested in lab conditions and in simulated field and BSL3-4 conditions. Product and system performance for these applications will be measured and evaluated as proposed in Phase I. At the conclusion of Phase II, specific applications and products will be selected for production based on prototype function and evaluation, as well as military and commercial needs. The selected products will then be re-designed and improved as necessary in preparation for commercial production. PHASE III DUAL USE APPLICATIONS: In phase III, we seek a simple manual system that can be used to efficiently prepare multiple samples without electricity. The system may utilize multichannel pipettes that are compatible with the capsule-like specimen container (developed in PHASE I) and may incorporate chemical fixation reagent kits (developed in PHASE II). A manual system will provide benefits by enabling remote field sample preparation without electricity. At the same time, the contractor should be able to provide an automated system that may require an electrical connection or battery power to prepare samples with minimal user operations. REFERENCES: 1. Suvarna KS, Layton C, Bancroft JD. Bancroft’s Theory and Practice of Histological Techniques. 7th Edition, Elsevier Health Sciences, 2013. http://www.us.elsevierhealth.com/bancrofts-theory-and-practice-of-histological-techniques-9780702042263.html 2. Kuo J (editor). Electron Microscopy, 2nd edition. Methods in Molecular Biology vol. 369. Humana Press, Totowa, New Jersey. 2007. http://theaasm.org/my_doc/pezeshki/E-Learning/E-Learning/E-BOOK/Electron%20Microscopy%20Methods.pdf 3. Goodman SL, Wendt KD, Kostrna M, Radi C, Capsule-Based Processing and Handling of Electron Microscopy Specimens and Grids. Microscopy Today, 2015. 23(05):30-37. http://www.microscopy-today.com/jsp/search/groupsearch.jsf KEYWORDS: Microscopy, Electron Microscopy, Specimen preparation, Pathology, Histology, Laboratory, Biocontainment
TECHNOLOGY AREA(S): Biomedical OBJECTIVE: The objective of this effort is to develop a portable, non-contact diagnostic imager that can be used by non-experts to provide quantitative metrics of tissue physiology that help guide burn triage in far-forward environments. DESCRIPTION: Quantitative detection of, for example, hemoglobin, tissue oxygen saturation, edema, and perfusion can be used to assess tissue health in an objective manner. During the initial assessment of wounds, triage is critical for the patient when determining fluid requirements and transportation decisions to distant care facilities. In the case of burns, early and accurate assessment of the burn depth and surface area in the first several hours/days after the burn is of high value. The standard of care remains visual inspection that is both subjective in nature and highly variable in terms of outcome, particularly with respect to the expertise and experience of the assessor. In the absence of an experienced burn specialist, it is critical to have tools capable of making quantitative assessments on the burn severity and burn healing in order facilitate the making of health care decisions [1]. Optical technologies have shown promise as a quantitative tool for burn assessment but the technology form factor to date remains appropriate only for large hospitals and burn centers [2]. To this end, a portable, non-contact imaging device that can be easily used by clinicians in the field is needed. The device must be able to image a large area (i.e. limb) and account for surface curvature, lighting, motion, and variations in skin architecture/tone. The method should not involve any contrast agents or contact with the patient. Usability of the device is paramount so that a non-expert with minimal training can implement it quickly. The footprint of the device should be such that it is portable and easily transported in a carrying-case between patients. Finally, the cost of such a device must be considered to ensure true translatability. Standardization of design and storage of data that enables integration with telemedicine concepts is also highly desirable. Ideally, the proposed device eventually could be expanded to other fields where expertise can vary at the first level of care. Beyond initial burn assessment, such a device could be used for debridement guidance, assessment of tissue viability, graft take, ulceration tracking, reconstructive flaps, and vascular surgery. Adaptations of current technologies like spectral imaging that address the portability issue are acceptable for this application. PHASE I: The main goal of the Phase I project is to demonstrate through analysis and proof-of-concept experiments the design feasibility of a portable non-contact diagnostic imaging system for assessment of burn wound severity. The work in this phase should expand on an existing technology or method that has shown efficacy for burn assessment in pre-clinical or clinical models. Proposed proof of concept work should address the main design considerations for a portable device to be used in far-field scenarios. In vitro measurements that demonstrate feasibility of design and reduce risk are highly encouraged. Phase I work will be assessed on the rigor of proposed design, in vitro testing, and the fit with unmet need. The ability of technology to translate to other areas of work will also be considered. PHASE II: A device based on Phase I design will be built and tested. The proposed device hardware should be systematically and rigorously tested in phantom or in vitro tests. Pre-clinical and/or clinical evaluation of device is required in pilot studies for assessment of burn depth and should be compared to current standards. Emphasis on study design should be to help guide triage of a burn patient. This phase should culminate with a plan for large-scale clinical trials that could be part of an FDA clearance/approval. PHASE III DUAL USE APPLICATIONS: The large-scale clinical trials planned in Phase II will be implemented. The device developed and tested in Phase II will be further developed to accommodate such trials and toward a commercial product. FDA communications will be initiated at this stage, so that FDA approval of the product will be more easily obtained when the commercial product is ready. Commercialization will begin either with the small company or with a commercial partner. USAISR would be significant at this stage to assist in transition of the product to military usage. Civilian applications would be similar to military ones in trauma involving burns. Role 2 application should be the goal for the military, with possible use at role 1. The device should be usable by civilian trauma first responders to be able to communicate data to hospitals while transporting patients. Additional important military and civilian applications would include monitoring graft and reconstructive flap viability, ulceration tracking, vascular surgery, and assessing and monitoring frostbite. REFERENCES: 1. L. C. D'Avignon, J. R. Saffle, K. K. Chung and L. C. Cancio, "Prevention and management of infections associated with burns in the combat casualty," J Trauma 64(3 Suppl), S277-286 (2008) 2. . M. Kaiser, A. Yafi, M. Cinat, B. Choi and A. J. Durkin, "Noninvasive assessment of burn wound severity using optical technology: a review of current and future modalities," Burns: Journal of the International Society for Burn Injuries 37(3), 377-386 (2011) KEYWORDS: Burn severity, Burn depth, spectral imaging, tissue viability, wound healing,
TECHNOLOGY AREA(S): Biomedical OBJECTIVE: To develop a multimodal imaging and diagnostic device to evaluate the localized relationship between the extent of airway injury and alterations in airway compliance. DESCRIPTION: Pulmonary compliance is an important parameter in respiratory physiology as it measures the lung’s ability to expand and contract. There is a critical need for more localized airway compliance measurements. Airway injuries sustained on the battlefield, such as inhalation airway injury in burn patients, or aerosolized toxic agents, are often difficult to diagnose at an early stage [1, 2]. Overall compliance measurements can be calculated from tidal volume and pressure measurements but are only approximate measures of pulmonary compliance related to loss of pressure during inspiration and expiration. Optical Coherence Tomography (OCT) has been demonstrated to have great potential to measure early airway injury, and it could be combined with other modalities. [3] Measurement of localized airway compliance in conjunction with functional imaging techniques could provide insights into the mechanism and progression of inhalation airway injury, and provide a potential diagnostic tool PHASE I: Define and design a prototype multimodal imaging and diagnostic system to demonstrate the feasibility for continuous, real-time diagnosis of airway injuries. Quantifiable parameters must be identified to assess the system’s capability in reliably identifying early-stage airway injuries. The solution should be affordable, portable and reliable. The proposed device should be suitable for use in role 2 military settings. Phase I shall also include planning and applying for IRB approval for phase II testing in human volunteers, should phase II be funded. At the end of Phase I, the deliverables will include: 1) a preliminary prototype multimodal imaging system for diagnosis of airway injury, including compliance measurement; and 2) a technical report with detailed description of the approach that establishes design and analysis of predicted performance of the end product. PHASE II: Develop and produce the prototype system defined in Phase I. Phase II will be used to plan and execute further development of the prototype into a commercially viable diagnostic product for functional imaging of airway injuries and measuring of airway compliance. The performer shall demonstrate the efficacy of the device in humans by imaging human volunteers. Phase II deliverables include: 1) a developed functional imaging and diagnostic system, 2) technical reports detailing performance measures and results of human volunteer studies, and 3) a proposed plan for future actions to make the system commercially available for military and civilian use, including but not limited to, cost analysis and timeline, and those activities necessary to achieve Food and Drug Administration (FDA) and other required regulatory approvals. PHASE III DUAL USE APPLICATIONS: In this phase, the performer shall refine and execute the commercialization plan proposed in Phase II and conclusively demonstrate that the functional imaging and diagnostic system meets the requirements of this topic. In this phase, the performer shall develop a roadmap and cost/time estimate for additional development and clinical study activities to make the technology commercially available for military and civilian use. It is likely the developed instrumentation will be validated for military use by the U. S. Army Institute for Surgical Research. Civilian markets will exist, for example, in the diagnosis of respiratory disorders such as asthma, emphysema, and chronic obstructive pulmonary disease. [3]. REFERENCES: 1. J.B.West, Respiratory Physiology, 9th edition, page 99, Walters Kluwer/Lippincott, Williams & Wilkins, 2012. (ISBN-13: 978-1609136406) 2. Walker, Patrick F. et al. “Diagnosis and management of inhalation injury: an updated review” 2015, online at 10.1186/s13054-015-1077-4 3. Chou, Lidek, et al. “In vivo detection of inhalation injury in large airway using three-dimensional long-range swept-source optical coherence tomography,” J Biomed Opt. 19(3) (Mar 2014): 36018. KEYWORDS: Inhalation injury, pulmonary compliance, multimodal imaging, portable diagnostic, lung diagnosis, functional imaging, airway OCT
TECHNOLOGY AREA(S): Biomedical OBJECTIVE: Develop and demonstrate a prosthetic foot that provides normalized biomechanics and function, with no external power requirements, for patients with below the knee amputation performing military relevant tasks. DESCRIPTION: Over 1600 Service Members have experienced major amputations since 2001 due to the Global War on Terror. It is of utmost importance that these individuals continue to receive advanced rehabilitative care, including prosthetic devices, that allows them to achieve their functional goals, including the possibility of returning to duty. The loss of the ankle/foot system due to amputation is critical as this joint and its associated musculature provide 39-46% of the power required for forward mobility [Farris 2012]. State-of-the-art passive prosthetic ankles provide good initial contact energy absorption and storage and some energy return, however they cannot provide the net positive work normally generated by a biological ankle [Laferrier 2010, Hafner 2002, Torburn 1990, Postema 1997]. Prosthetic feet relying on passive energy storage and return release less than one-half the mechanical energy and less than one-eighth the peak mechanical power normally generated by the ankle musculature during gait [Zmitrewicz 2007]. The current design of passive prostheses represents a trade-off made by manufacturers between the conflicting requirements for energy return and ankle range of motion. The limited range of motion at the prosthetic ankle allows the carbon fiber to deflect, thereby storing and returning some power. Although the energy return of the prosthetic components is limited, it provides some benefit towards the ability to perform activities of daily life and decreasing the metabolic demand of these users. While an articulating ankle with larger range of motion would solve some problems associated with negotiating uneven surfaces more comfortably and perhaps safely, it would be at the cost of reducing the energy return to almost zero which would severely affect quality of life. The creation and use of powered ankle/foot systems has shown normalization of some biomechanical and metabolic metrics [Herr 2012; Hitt 2010]. However, the limitations of these devices include cost, resistance to the elements, noise, and battery life. A non-powered, low cost ankle/foot system capable of providing normative ankle function would be an ideal alternative. PHASE I: Conceptualize and design an innovative solution for a prosthetic foot that provides normalized biomechanics and function with no external power. The design should aim to restore 80% of the range of motion and power generation of an uninjured anatomical ankle [Herr 2012, Gitter 1991, Cherelle 2014]. Designs should be able to interface with current prosthetic components (i.e. easily attach to prosthetic sockets replacing the user’s current device), and be reimbursable to the current level of energy storage and return prosthetic feet. The required Phase I deliverables will include: 1) a research design for engineering the device and 2) A preliminary prototype with limited testing to demonstrate proof-of-concept evidence that demonstrates normalized biomechanics and function for patients with transtibial amputation. Other supportive data may also be provided during this 6-month Phase I effort. PHASE II: The investigator shall design, develop, test, finalize and validate the practical implementation of the prototype system that implements the Phase I methodology for a prosthetic foot that provides normalized biomechanics and function with no external power, over this effort. The investigator shall also describe in detail the transition plan for the Phase III effort. The testing and practical implementation of the prototype system should be relevant to Service members who have experienced lower limb amputations. These patients are often young and have previously demonstrated Return to Duty, occupation, and other life activities requiring robust and durable technologies. The demonstration of prototype systems should be rigorous enough to demonstrate the abilities of the system to function in these environments beyond current capabilities. PHASE III DUAL USE APPLICATIONS: The investigator shall work with commercial partners and military clinics (for example, a military treatment facility that treats patients with amputation. The 3 main centers are Walter Reed National Military Medical Center, San Antonio Military Medical Center, and the Naval Medical Center – San Diego) to develop a final commercial product (no power prosthetic foot) that will allow for normalized biomechanics and function for patients with transtibial amputation. REFERENCES: 1. Farris DJ, & Sawicki GS. (2012). J R SOC INTERFACE, 9(66), 110. 2. Hafner BJ, Sanders JE, Czerniecki JM, Fergason J (2002). J REHABIL RES DEV, 39(1), 1-11. 3. Herr HM, and Grabowski AM (2012). P ROY SOC B-BIOL SCI, 279, 457-464. 4. Hitt JK, Sugar TG, Holgate M, Bellman R. (2010). J MED DEVICE, 4(1). 5. Laferrier JZ, and Gailey R (2010). PHYS MED REHABIL CLI, 21, 87-110. 6. Postema K, Hermens H, de Vries J, Koopman H, Eisma W (1997). PROSTHET ORTHOT INT, 21, 17-27. 7. Torburn L, Perry J, Ayyappa E, Shanfield SL (1990). J REHABIL RES DEV, 27(4), 369-84. 8. Zmitrewicz RJ, Neptune RR, Sasaki K (2007). J BIOMECH, 40, 1824-1831. 9. Gitter A, Czerniecki JM, DeGroot DM (1991). AM J PHYS MED REHAB, 70(3), 142-148. 10. Cherelle P, Mathijssen G, Wang Q, Vanderborght B, Lefeber D. (2014). AD MECH ENG, 6. KEYWORDS: biomechanics, prosthetic foot, power, function, transtibial amputation DHP - Yüklə 43,39 Kb. Dostları ilə paylaş:
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