SBIR-STTR Award

Sepsis, an uncontrolled systemic inflammatory immune response to local infection by bacteria or fungi, is responsible for more deaths than prostate cancer, breast cancer, and AIDS combined, accounts for more than 40% of ICU costs, and is the most expensive inpatient condition in the U.S. (~$20B in annual U.S. healthcare expenditures in 2011). While it has been demonstrated that the time to initiating aggressive treatment is critical to improving outcomes (currently ~40% mortality) and decreasing costs (>$22,000/case), the field suffers from a lack of compelling early diagnostic tools. CytoVale aims to improve the sepsis treatment paradigm by offering a platform to detect abnormal systemic inflammation at initial presentation. Our diagnostic platform will offer a cost-effective,robust, and rapid sample-to-decision assay (< 5 minute), in which activated white blood cells that are indicative of uncontrolled systemic inflammation are identified in a label-free manner. Inorder to impact quality of care, the instrument must be situated at the point-of-care (POC), where it can provide rapid feedback to physicians. Currently, this is not feasible, due to manual operations required to prepare samples for the assay. Primarily, this involves removal of red blood cells, debris, and large concentrations of protein, which confound CytoVale's test. Here, we propose to automate the process of sample preparation by developing an integrated module which makes use of a microfluidic technology termed Rapid Inertial Solution Exchange (RInSE). Primarily, this will enable identification and triaging of patients at earlier sepsis disease stage from a finger-prick of blood. Additional cost and patient comfort benefits arise from the ability t track the course of disease and design treatments specific to patient response, saving days spent in the hospital and associated costs. CytoVale's test identifies activated cells through automated high-speed measurements of their mechanical properties, purportedly linked to their ability to infiltrate tissue to response to infection. The first aim of the proposal will contribut to an understanding of the effects of sample preparation, specifically red blood cell lysis, on this class of emerging biomarkers. Furthermore, the microfluidic sample preparation module will be more broadly useful amongst other cell analysis methods, such as traditional flow cytometry. Combined, these aims will expand accessibility of powerful cell-based assays at the point-of-care.

Thesaurus Terms:
Accident And Emergency Department;Accounting;Acquired Immunodeficiency Syndrome;Adoption;Antibiotics;Area Under Curve;Automation;Bacteria;Base;Biological Assay;Biological Markers;Blood;Blood Specimen;Blood Volume;Buffers;Cells;Cessation Of Life;Chromatin;Clinical;Clinical Research;Clinical Trials;Cohort;Commercialization;Complex;Cost;Cost Effective;Cytolysis;Cytometry;Data;Databases;Detection;Development;Diagnosis;Diagnostic;Disease;Drops;Electrodes;Empowered;Engineering;Erythrocytes;Etiology;Event;Excision;Expenditure;Feedback;Fingers;Flow Cytometry;Focal Infection;Fungus;Goals;Grant;Healthcare;Heart;Hospitals;Immune Response;Improved;Infection;Inflammation;Inflammatory;Injection Of Therapeutic Agent;Inpatients;Instrument;Label;Leukocytes;Link;Liquid Substance;Lung;Malignant Breast Neoplasm;Malignant Neoplasm Of Prostate;Malignant Neoplasms;Manuals;Measurement;Measures;Mechanics;Methods;Metric;Microfluidic Microchips;Microfluidics;Molds;Monitor;Mortality Vital Statistics;Nanofabrication;Neonatal Sepsis;Next Generation;Nuclear Envelope;Operation;Organ Failure;Outcome;Output;Participant;Patient Triage;Patients;Phenotype;Physicians;Pleural Effusion Disorder;Point Of Care;Population;Preparation;Procedures;Process;Property;Proteins;Protocols Documentation;Public Health Relevance;Quality Of Care;Reagent;Research;Research Clinical Testing;Response;Sampling;Scale Up;Science;Screening;Sepsis;Series;Small Business Innovation Research Grant;Solutions;Specificity;Speed (Motion);Staging;Standard Of Care;Suspension Substance;Suspensions;System;Technology;Testing;Therapy Design;Time;Time Use;Tissues;Tool;Translational Medicine;Triage;Whole Blood;Work;

Sepsis, an uncontrolled systemic inflammatory immune response to local infection by bacteria or fungi, is responsible for more deaths than prostate cancer, breast cancer, and AIDS combined, accounts for more than 40% of ICU costs, and is the most expensive inpatient condition in the U.S. (~$20B in annual U.S. healthcare expenditures in 2011). While it has been demonstrated that the time to initiating aggressive treatment is critical to improving outcomes (currently 30-50% mortality) and decreasing costs (>$22,000/case), emergency medicine physicians suffer from a lack of compelling diagnostic tools for detection of sepsis in the emergency department (ED), where >80% of sepsis cases originate in the hospital. CytoVale aims to improve the sepsis treatment paradigm by offering a platform to detect abnormal systemic inflammation at initial presentation. Our diagnostic platform will offer a cost-effective, robust, and rapid sample-to-decision assay (< 10 minutes), in which activated white blood cells that are indicative of uncontrolled systemic inflammation are interrogated in a label-free manner. In order to impact quality of care, the instrument must be situated at the point-of-care (POC), where it can provide rapid results to impact patient care. Currently, this is not feasible, due to manual operations required to prepare samples for the assay (e.g., centrifugation, pipetting) and the lack of an in- sample calibration. Here, we propose to capitalize on the success of our Phase 1 progress of automating the process of sample preparation by now developing a fully integrated module that combines the sample preparation and deformability cytometry microfluidics into a single cartridge and instrument. This will allow for the identification and triaging of patients earlier in their disease process at the ED POC from a finger-prick of blood. Additional cost and patient comfort benefits arise from the ability to track the course of disease and design treatments specific to patient response; saving days spent in the hospital and associated costs. Cytovale also proposes to develop and integrate a deformable sample control. Mechanical standard particles will be used as internal controls within each sample run, to ensure fidelity of the instrument readings and diagnostic accuracy. Not only will this help verify reliability and consistency of experiments, but will also supply a much needed calibration particle to the growing field of cellular biophysics. Combined, these aims will expand accessibility of powerful cell-based assays at the POC.

Public Health Relevance Statement:
Project Narrative Sepsis, an uncontrolled systemic response to local infection by bacteria or fungi, is responsible for more deaths than prostate cancer, breast cancer, and AIDS combined, accounts for more than 40% of ICU costs, and is associated with ~$20B in annual U.S. healthcare expenditures. There are no diagnostics that can detect sepsis early in its course in the emergency department, when it is treatable with readily available antibiotics and fluids, and before the onset of major organ failure which is detected by current diagnostics. We propose to integrate complete automation of the first ED point of care sepsis diagnostic assay, to enable rapid detection of sepsis at the point that will maximally improve patient outcomes from this deadly disease.

NIH Spending Category:
Bioengineering; Biotechnology; Clinical Research; Emergency Care; Health Services; Hematology; Septicemia

Project Terms:
Accident and Emergency department; Accounting; Acquired Immunodeficiency Syndrome; American; analog; Antibiotics; Area; Automation; Bacteria; base; Biological Assay; Biomechanics; Biophysics; Blood; Blood specimen; Caliber; Calibration; Cause of Death; Cells; Centrifugation; Cessation of life; Chest; Clinical; clinical decision-making; Clinical Research; cost; cost effective; Cytometry; Data; Detection; Development; Diagnosis; Diagnostic; diagnostic accuracy; diagnostic assay; Diagnostic tests; Disease; Disease Progression; Emergency Department patient; Emergency Medicine; Ensure; Expenditure; Fingers; Focal Infection; Functional disorder; fungus; Grant; Healthcare; Hospitals; Hour; Imaging technology; Immune; immune activation; Immune response; Immune system; improved; improved outcome; indexing; Individual; Infection; Inflammation; Inflammatory; Inpatients; instrument; interest; internal control; Interview; Killings; Label; leukocyte activation; Leukocytes; Liquid substance; malignant breast neoplasm; Malignant neoplasm of prostate; Manuals; Measurement; Measures; Mechanics; Methods; Microfluidics; Monitor; mortality; Noise; novel diagnostics; One-Step dentin bonding system; operation; Organ; Organ failure; Outcome; particle; Patient Care; Patient Triage; Patient-Focused Outcomes; Patients; Performance; Phase; Physicians; point of care; point-of-care diagnostics; Population; Preparation; prevent; Process; Property; Quality of Care; rapid detection; Reading; Reagent; Reference Standards; research study; response; Running; sample collection; Sampling; screening; Sepsis; septic; Severities; Signal Transduction; single cell analysis; Societies; Specificity; Speed; Staging; standard of care; Standardization; success; System; Techniques; Testing; therapy design; Time; tool; Triage; usability; Whole Blood