A New Method for Acoustic Blood Oxygen Level Dependent (BOLD) imaging

About This Grant

1 Project Summary: Neonatal Hypoxic Brain Injury (HBI) represents critical medical conditions 2 that require continuous monitoring of brain oxygenation to facilitate timely intervention and 3 predict future outcomes. Traditional treatments, such as whole-body cooling, have not 4 significantly reduced high mortality and disability rates, highlighting the urgent need for 5 advanced neuromonitoring tools for localized interventions. Our team believes a solution lies in 6 serial, noninvasive monitoring of blood oxygenation consumption in the brain at a locoregional 7 level. This method could serve as an invaluable tool for assessing brain function and managing 8 treatment in real-time. We are therefore exploring the development of a pioneering, noninvasive 9 ultrasound-based tool that would enable bedside monitoring of deep brain tissue oxygenation. 10 Here, we propose to develop a first-in-kind technology that enables Acoustic BOLD imaging 11 using oxygen-responsive ultrasound contrast agents as biosensors for bedside monitoring. 12 We have designed tiny microbubbles comprised of functional hemoglobin protein surrounding an 13 air-filled core (HbMBs, <10 µm in diameter). The HbMBs introduced into circulation generate 14 sound when an ultrasound field is applied, making them detectable on clinical ultrasound 15 scanners. Hemoglobin is an endogenous oxygen-binding protein found in red blood cells, serving 16 as the body's primary oxygen transporter. In its ferrous state, the iron-containing heme group will 17 reversibly bind to oxygen, altering the protein structure. We hypothesize that these structural 18 changes in the hemoglobin would change the mechanical properties of the microbubble shell (and 19 therefore the acoustic properties), which can be correlated to blood oxygen levels. Indeed, our 20 preliminary data shows that we can successfully generate hemoglobin-stabilized air-filled bubbles 21 capable of reversibly binding oxygen and changing their acoustic properties. Acoustic differences 22 are detectable using standard quantitative contrast-enhanced ultrasound (qCEUS) imaging and 23 passive cavitation detection (PCD) techniques. Our preliminary data demonstrates proof-of- 24 principal that HbMBs are viable acoustic oxygen sensors that have the potential to provide low- 25 cost and reliable alternatives to Optical and MRI-based BOLD imaging techniques. The overall 26 goal of our proposal is to (1) further develop this system to test the accuracy, reproducibility and 27 sensitivity in vitro and in vivo, (2) characterize the HbMBs pharmacokinetics, immune response, 28 and biosafetly and (3) demonstrate quantitative methods of assessing blood oxygen levels in vivo 29 using pig hypoxia/hyperoxia model and advanced imaging strategies to isolate oxygenation and 30 perfusion information in the microvasculature regions.