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Longitudinal Assessments of Placental Oxygenation and Perfusion Using Ultrasound and Photoacoustics.

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? DESCRIPTION (provided by applicant): The accurate assessment of placental perfusion and oxygenation throughout pregnancy is key to understand the role of the suboptimal placental development on pregnancy progression and outcome, including early detection of pregnancies at risk of intrauterine growth restriction (IUGR) or preeclampsia. Photoacoustic imaging (PA) is preclinical and emerging clinical tool that combines optical contrast of photoacoustic laser technology with the low acoustic scattering and high spatial resolution of micro-ultrasound. PA technique allows accurate measurements of tissue oxygen saturation (sO2) due to the differences in absorption spectra for oxygenated and deoxygenated hemoglobin. By using photoacoustic features of VEVO LAZR high resolution ultrasound system (VisualSonics) we will investigate the sensitivity and accuracy of the PA imaging for the measurements of placental oxygenation and perfusion. The hypothesis of our studies is that PA imaging provides accurate assessments of placental sO2 and hemoglobin concentration in the placenta. Our proof of concept key preliminary studies demonstrate that a difference in placental sO2 can be detected in pregnancy associated with IUGR compared to normal pregnancy. Specific Aim 1. To investigate the sensitivity of PA imaging for the assessments of placental sO2 in vivo using 2D and 3D modes. Regional differences in sO2 across placenta as well as longitudinal changes throughout pregnancy will be established starting from the day 9 when the placenta can be clearly visualized by ultrasound (days 9, 11, 14, 16, 18) in response to different levels of breathing oxygen. Placental sO2 levels will be correlated with fetal brain sO2 and fetal heart rate to establish whether differences in fetal brain sO2 simultaneously detected with placental sO2 can be established using PA imaging (Aim 1A). The application of contrast agents such as nanoparticles to improve the sensitivity of PA imaging and allow the detection of placental hypoxia by labeling hypoxic cells will be tested in Aim 1B. In Aim 1C, we will establish whether PA imaging is sensitive to detect changes in placental sO2 in a mouse model of IUGR versus mouse with normal late pregnancy. Specific Aim 2. To test the sensitivity of PA imaging for detecting placental vascular development during normal pregnancy. We will test the hypothesis that perfusion of the placenta with non-targeted contrast agents improves 1) the ability of ultrasound to determine placental length, diameter and 3D volume, and 2) the detection of alterations of perfusion patterns in response to different concentrations of breathing oxygen. We will also establish whether microbubble-based contrast agents targeted to VEGFR2 or VCAM-1 enhances the ability of ultrasound to detect the development of placental vasculature in pregnancy. Specific Aim 3. To test the sensitivity and accuracy of PA imaging for sO2 measurements in vitro using tissue mimicking blood phantom and mathematical modeling of sO2. Overall, our studies will provide a necessary validation of PA imaging for the assessments of placental oxygenation/hypoxia during pregnancy and will offer an avenue for future clinical application of this technology.
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