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

 描述(由申请人提供)：准确评估整个妊娠期间的胎盘血流和氧合情况是了解胎盘发育不佳对妊娠进展和结局的作用的关键，包括早期发现有宫内生长受限(IUGR)或先兆子痫风险的妊娠。光声成像(PA)是一种结合了光声激光技术的光学对比度和微超声的低声散射和高空间分辨率的临床前和新兴的临床工具。由于氧合和去氧血红蛋白的吸收光谱不同，PA技术可以准确测量组织氧饱和度(SO2)。利用VEVO LAZR高分辨率超声系统(Visualsonics)的光声特性，我们将研究PA成像在测量胎盘氧合和血流灌注方面的敏感性和准确性。我们研究的假设是PA成像提供了对胎盘SO2和胎盘中血红蛋白浓度的准确评估。我们的概念验证关键的初步研究表明，与正常妊娠相比，与IUGR相关的妊娠可以检测到胎盘SO2的不同。具体目的1.探讨二维和三维模式下PA成像对活体胎盘SO2检测的敏感性。从第9天开始，随着呼吸氧气水平的不同，超声波可以清楚地显示胎盘(第9、11、14、16、18天)的胎盘，从第9天开始，胎盘中二氧化硫的区域差异以及整个怀孕期间的纵向变化将被确立。胎盘二氧化硫水平将与胎脑二氧化硫和胎心率相关，以确定是否可以使用PA成像(目标1A)来确定与胎盘二氧化硫同时检测到的胎脑二氧化硫的差异。应用纳米颗粒等造影剂来提高PA成像的灵敏度，并通过标记缺氧细胞来检测胎盘缺氧，将在AIM 1B中进行测试。在目标1C中，我们将确定PA成像是否能灵敏地检测IUGR小鼠模型与正常晚期妊娠小鼠胎盘SO2的变化。具体目的2.探讨PA显像检测正常妊娠胎盘血管发育的敏感性。我们将测试这样一种假设，即用非靶向造影剂对胎盘进行灌注可以提高1)超声确定胎盘长度、直径和3D体积的能力，以及2)检测不同浓度的呼吸氧对灌注模式的改变。我们还将确定靶向VEGFR2或VCAM-1的微泡造影剂是否增强了超声检测妊娠期间胎盘血管发育的能力。具体目的3.利用组织模拟血液模型和SO2的数学模型，测试PA成像在体外测量SO2中的灵敏度和准确性。总体而言，我们的研究将为妊娠期间胎盘氧合/缺氧的评估提供必要的PA成像验证，并为该技术的未来临床应用提供一条途径。

 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.