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Olfactory Neuroepithelium Functional Diagnostic Tool


OUSD (R&E) MODERNIZATION PRIORITY: General Warfighting Requirements (GWR)




OBJECTIVE: To develop a non-invasive diagnostic device that can be used to determine the cellular and functional characteristics of olfactory neuroepithelium with limited or no anesthesia. The device should be able to determine thickness of mucus on top of the mucosa and then be able characterize important properties of the cellular layers of the olfactory cleft mucosa as has been demonstrated with optical coherence tomography (OCT) and confocal laser endomicroscopy (CLE) in the pulmonary tract. This would include proportion of supporting cells, fibrosis, and neuronal composition. The ability to assess olfactory neuroepithelium cellular structure enables assessment of the degree of insult from injury, leading to better treatment and improved patient outcomes. The resulting diagnostic device (medical product) will be employed at level III or IV care for diagnostic assessments after injury.


DESCRIPTION: Modern warfare exposes members to significant volatile inhalational injury risk. Many members return from deployments reporting a diminished sense of smell from burn pit exposure, oil field vapors, exposures to minute quantities of harmful battlefield chemicals, and other onsite/uncharacterized chemical exposures. The current COVID pandemic has significantly increased the number of permanent hyposmia/dysosmia cases occurring in active-duty personnel to the point of olfactory dysfunction becoming a concerning risk for duty limitation8. As a poignant example of this, Joint Base San Antonio Ear, Nose and Throat (ENT) referrals for active duty olfactory dysfunction have gone from a handful a year, to 2-3 per week. Modern testing techniques for olfactory dysfunction currently are very elementary and produce poor quality objective data on which to base treatments. These tests simply report a percent correct of common odors recognition with no insight regarding mechanism of injury. This ability to differentiate is critical to ensure optimal therapeutic strategy. For example, anosmia due to allergies or sinusitis responds to steroids and other anti-inflammatory therapies to reduce edema in the local microenvironment. This contrasts with COVID associated anosmia, which is due to injury to supporting cells, resulting in neuronal death. COVID associated anosmia does not respond to anti-inflammatory therapies and likely requires therapies targeting neuronal regeneration.


The primary role of olfaction in the military is for supporting “threat assessment.” The following career fields have expressed concerns to us over the years regarding loss of sense of smell: Military Police and Security Personnel (smell of alcohol on breath, vapors from an investigation scene), Firemen (smell of smoke, methane, other volatiles), Food Safety personnel (responsible for preventing food poisoning related to feeding vast numbers of personnel/trainees), Medical Workers (rely on sense of smell for sterility assessment, diagnostics), and Flight Line personnel (Jet Fuel leakage and other industrial chemical hazards). Outside of basic sense of smell tests and subjective questionnaires, there are no reliable imaging tools to assess any key characteristic of the sense of smell. We propose to develop a new technology for olfactory neuroepithelium assessment that will include an objective assessment of the health and viability of the olfactory cleft mucosa. Specifically, we desire a technology that can differentiate the following layers in terms of thickness, and other key material properties: mucus, epithelium, lamina propria, and potentially the olfactory bulb. We are impressed with the potential of both OCT (Optical Coherence Tomography) and CLE (Confocal Laser Endomicroscopy) technologies for this capability, and are open to new and novel technological solutions that may offer better solutions for improving patient outcomes. With this innovation, health care providers will be provided a tool to obtain essential objective data required to screen for disease and to recognize when treatments are having a subclinical effect.


PHASE I: During Phase one, determine and define the efficacy of the proposed technology that can determine layer thickness and material properties of the olfactory neuroepithelium. The proposed technology will have not have the potential to damage the mucosa or chemosensory structures being examined. Design/develop an innovative concept along with limited testing of potential materials. The product will be evaluated by Otolaryngologists, Allergists and Neurologists at role 3-4 clinical settings. Design requirements may include ease of use, minimal equipment or activation process and be delivered in a minimally invasive manner. It must be mobile, not cause pain or bleeding, able to be used without physically disturbing the structure it is measuring, have ease of storage (heat and cold tolerance) and be applied in vivo (no biopsy required to perform measurements). Demonstration of a prototype is desirable with some early in vitro data using rodent cultures. The product will report key histologic metrics to include: epithelial layer thickness, proportion of supporting cells, neuronal density and organization and inflammatory burden in the spectrum from normal olfaction to anosmia. The product should have function that meets existing output measures of similar technology applied to pulmonary respiratory mucosa.


PHASE II: Detail analysis of the selected device that will include optimal performance properties that are safe and perform according to the specifications listed below. The device should be designed to be utilized to minimize or avoid causing severe discomfort, bleeding, or mucosal disruption with use. In vivo efficacy will be established murine models of anosmia. Validation of efficacy will be gross histologic confirmation.The device will report key histologic metrics to include: epithelial layer thickness, proportion of supporting cells, neuronal density and organization and inflammatory burden in the spectrum from normal olfaction to anosmia. Validation of efficacy will be gross histologic confirmation. Clinical experts with insight into olfactory dysfunction and relevant patient populations should be consulted during optimization and animal validation.


PHASE III DUAL USE APPLICATIONS: Potential commercial and clinical partners for Phase III and beyond should be identified, and a detailed explanation should be provided for how the small business will obtain a monetary return on investment. Awardees will seek to develop a useable prototype for DOD role 3 and 4 environments. They will develop a strategy to lock in the final design (freeze and bridge the gap between laboratory-scale innovation and entry into a recognized FDA regulatory pathway leading to commercialization of the product that will be made available for purchase by the military health system and private sector. Close communication with military surgeons on the development on the product should be considered. Additional customers will likely be academic referral centers capable of validating a large number of patients with olfactory complaints. Functional prototypes will enable development and funding of clinical trials to assess efficacy of the devices and optimize functionality, performance, and safety. Small business should have a strategy in place to secure funding from the private sector and partnering with other medical device companies as needed to reduce costs and risk while improving product availability and capabilities. Imaging companies in the OCT space (e.g. OptoVue) are likely partners to streamline development and testing in humans. Given the worldwide impact of anosmia, funding should be sought from the World Health Organization (WHO).



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KEYWORDS: Olfactory Dysfunction, Anosmia, Hyposmia, Dysosmia, Burn Pit

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