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Point-of-care Monitoring of the Host-Pathogen Interaction during Infection

Description:

 
 

PROPOSALS ACCEPTED: Phase I and DP2. Please see the 16.2 DoD Program Solicitation and the DARPA 16.2 Direct to Phase II Instructions for DP2 requirements and proposal instructions.

TECHNOLOGY AREA(S): Biomedical

OBJECTIVE: Develop point-of-care technologies to monitor and characterize host-pathogen interactions during acute severe infection.

DESCRIPTION: There is a critical DoD need to develop a system that could be used at the point of care for monitoring in near real time host-pathogen interactions that would enable personalized therapeutic interventions during acute severe infection. Proposed approaches must go beyond traditional techniques for diagnosis based on microbiological testing, clinical signs, symptoms, and physiology to enable more targeted and appropriate interventions. Parameters of interest include, but are not limited to nucleic acids, cytokines, coagulation factors, hemopexin, and pathogen-associated molecular pattern (PAMP) molecules. The proposed technique must be capable of frequently measuring analytes and be in a format suitable for point-of-care use. During the course of severe clinical infection, the fluctuating status of patients requires frequent monitoring that ultimately informs treatment. Patient outcomes are determined by the invading pathogen(s), subsequent host response, and therapeutic intervention. For example, sepsis arises from an exuberant host response to infection that results in collateral organ and tissue damage. This syndrome represents a major health challenge and is one of the most common causes for admission into intensive care units (ICU). Blood culture is considered the gold standard for diagnosis and identification of pathogens in the bloodstream, but is insensitive and suffers from a long turnaround time.

PHASE I: Demonstrate feasibility of the approach in a breadboard configuration. A detailed design and manufacturing plan, animal testing plan, regulatory plan, and commercialization strategy shall be delivered with the final report.

PHASE II: Develop prototypes of the system. The performance characteristics of the system shall be evaluated using clinically relevant samples. Manufacturing of the system should be done under GMP conditions. A regulatory package should be drafted with the requisite supporting information. The device prototype will be required to meet the following specifications:

• Specimen Matrix: Blood (< 50 µL drop) • Limit of Detection: Dependent on analyte (specify & justify in proposal) • Dynamic Range: Dependent on analyte (specify & justify in proposal) • Error and Uncertainty: Specify & justify in proposal (compared to gold standard measurement and across multiple measurements) • Test Turnaround Time (TAT): < 30 minutes • Ease of Use: Low complexity; < 5 steps by user with one timed step requiring < 5 minutes of user intervention • User Interface: Results displayed on screen with capability to save and recall previous results • Power: AC and battery (> 8 hour lifetime; > 15 tests between charges) • Training: Minimal; instructions and graphical aides sufficient for user operation • Storage: Reagents do not require cold-chain and shelf stable > 12 months • Form Factor: Handheld device for sample preparation and measurement • Communications Interface: USB with computer for data upload/download

PHASE III DUAL USE APPLICATIONS: A clear plan towards FDA approval for the device should be implemented and additional testing to meet FDA requirements will be completed. Additional funding may be provided by DoD sources, but the awardee must also look toward other government or civilian funding sources to continue the process of translation and commercialization. If successful, this device would have clinical utility in both civilian and military settings. Acquisition customers include the US Army Medical Research and Materiel Command (MRMC) and Defense Health Agency (DHA).

REFERENCES:

  • Jain, A. A shear gradient-activated microfluidic device for automated monitoring of whole blood haemostasis and platelet function. Nature Communications 7 (2016).
  • Kellum, JA. Understanding the inflammatory cytokine response in pneumonia and sepsis. Arch Internal Medicine 15, 1655 – 1663 (2007).
  • McHugh, L. A molecular host response assay to discriminate between sepsis and infection-negative systemic inflammation in critically ill patients: Discovery and validation in independent cohorts. PLoS Medicine 12, 1 – 35 (2015).
  • Oved, K. A novel host-proteome signature for distinguishing between acute bacterial and viral infections. PLoS One 10, 1 – 18 (2015).
  • Service, RF. Will biomarkers take off at last? Science 321, 1760 (2008).
  • Taslik, EL. Host gene expression classifiers diagnose acute respiratory illness etiology. Science Translational Medicine 8, 322ra11 (2016).

KEYWORDS: Host-pathogen interaction; point-of-care; prognostic; diagnostic; pathogen-associated molecular pattern (PAMP) molecules; nucleic acid detection; hemopexin; cytokines

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