A Rapid, Near Patient System for Small Blood Volume Testing of Ammonia, Glutamine and Glutamate to Support Recurrent Monitoring of Acute Neonatal Hyperammonemia - ABSTRACT
A Rapid, Near Patient System for Low Blood Volume Testing of Ammonia, Glutamine and Glutamate to
Support Recurrent Monitoring of Acute Neonatal Hyperammonemia (SBIR Phase I)
In newborns, hyperammonemia (plasma ammonia >150 μmol/L) is often the first symptom of an underlying
urea cycle disorder (UCD), fatty acid oxidation defect or severe liver disease, and affects an estimated 1 in
8,000 births. Clinical symptoms may present as early as the first few days of life and, without prompt medical
attention, can rapidly lead to serious brain injury or death. Acute treatment for hyperammonemia includes
simultaneous diagnostic evaluation to distinguish the physiologic basis for ammonia accumulation and
therapeutic interventions to reduce plasma ammonia levels and prevent permanent neurologic damage. Given
the potential severity of symptoms and the rapid rate of disease progression, expedited testing is vital to the
survival of affected newborns. Unfortunately, diagnostic testing for hyperammonemia is currently challenging in
newborns due to the relatively large blood volume (>3mL) needed for multiple analytes, the requirement for
recurrent testing during therapy and technical limitations for ammonia assays. There is a compelling need for
better methods to rapidly diagnose and monitor hyperammonemia in newborns using low blood volumes.
We propose to develop a novel digital microfluidic system (FINDER) for the rapid, near patient measurement of
ammonia, glutamine and glutamate in newborns from very low volumes of whole blood (<50 μl for all assays).
Glutamine and glutamate are critical for ammonia homeostasis and serve as useful biomarkers in certain
UCDs. Through this Phase I SBIR project, we will develop sensitive, automated assays capable of measuring
all three analytes within 20 minutes. The FINDER Hyperammonemia test panel will allow clinicians to perform
repeated testing during acute treatment of blood-volume limited neonates without increasing the risk for
iatrogenic anemia.
The Phase I Specific Aims include: (1) develop novel enzymatic assays for ammonia, glutamine and glutamate
measurement using the FINDER digital microfluidic cartridge; (2) optimize assay conditions and determine
preliminary analytical sensitivity and specificity; and (3) feasibility demonstration using patient plasma samples.
The key milestone for progression to Phase II will be the successful demonstration of all assays on-cartridge
with acceptable sensitivity and precision. In future Phase II efforts, we will expand the panel to include
additional analytes (ketones, glucose and/or liver function tests), establish reagent drying protocols for the
multiplexed assay and perform full analytical and clinical validations. We will seek FDA approval of the final
product, which will initially be marketed for use in newborn patients in U.S. hospitals, with a potential future
market towards older patients with known metabolic disorders, who may benefit from the rapid, low blood
volume features of the platform.
