1. Eunice Kennedy Shriver National Institute of Child Health & Human Development receives a NIH Grant for Quantitative Biophontonics for Tissue Characterization and Function

    Eunice Kennedy Shriver National Institute of Child Health & Human Development receives a NIH Grant for Quantitative Biophontonics for Tissue Characterization and Function

    Eunice Kennedy Shriver National Institute of Child Health & Human Development receives a 2018 NIH Grant for $741,019 for Quantitative Biophontonics for Tissue Characterization and Function. The principal investigator is Amir Gandjbakache. Below is a summary of the proposed work.

    Monitoring the placenta oxygenation is critical to ensure a healthy pregnancy outcome. Abnormalities in placental oxygenation has been associated with preeclampsia and intrauterine growth restriction, fetal hypoxia, asphyxia, and cerebral palsy. Currently, there are no patient-friendly devices to measure the oxygenation of the anterior placenta. Therefore, it is crucial to have a quantitative understanding of placental oxygenation. Functional Near Infrared Spectroscopy (fNIRS) provides a technique that can address these challenges with its wearable, wireless capability that is convenient for dynamic monitoring. In parallel to the in-vivo studies, we are also interested in investigating placenta at cellular level to control the oxygen levels and understand its effect on cell metabolism. We intend to 1) find the baseline for the normal pregnancies standardize the oxygenation data across pregnancies, 2) correlate the oxygenation data with the pregnancy outcomes and 3) study placental cell metabolism in-vitro at physiologically relevant variations of oxygen level using a novel biophotonic methodology, Dynamic Full Field Optical Coherence Tomography (DFFOCT). For the in-vivo study, we created a fast, non-invasive and wearable device to allow continuous measurement of the oxygenation of the anterior placenta in a subject-friendly environment. This light-weight compact system can be positioned at different abdominal locations for efficient and localized measurement of oxygenation. The NIRS device uses the light in near infrared region (760 and 850 nm) that is sensitive to changes in oxy-hemoglobin and deoxy-hemoglobin and consists of two detectors and three sources to probe different tissue depth and distinguish the oxygenation between maternal and placental tissue. We have investigated the efficiency of device to accurately separate the oxygenation of the maternal and the placental tissue and to account for differences in maternal tissue such as skin color and fat content. Since the light passes through several tissue compartments, we have developed the multi-layer model based on Monte Carlo simulation that includes optical properties of skin, fat, uterus and placental tissue to account for scattering due to fat thickness and absorption due to melanin. For precise calculation of the oxygenation prior knowledge of the optical properties of the given tissues such as scattering (how much tissue scatters the light) and absorption (how well tissue absorbs the light) is needed. To find the optical properties of the placenta we use dual wavelength LED source with photodiode array unit built in-house. The attenuation coefficient (as a function of scattering and absorption coefficient), for several near infrared wavelengths, is calculated based on the reflection curve (photon count as a function of source-detector distance) from tissues with and without blood. Using Monte Carlo simulation along with our multi-layer model, we develop the system that takes parameters such as skin color and fat thickness into the calculation of oxygenation index. In collaboration with Maternal-Fetal Medicine, Imaging, and Behavioral Development Affinity Group (Dr. Roberto Romero) at NICHD, Wayne State University, and USUHS we test our device through pilot studies. We have started our first pilot study with Wayne State University, where we measure the oxygenation of the placenta during the last trimester in normal pregnancies to find a baseline of placenta oxygenation. Meanwhile, we refine our data analysis software by incorporating anatomical data from subjects. We expect to provide earlier detection of pregnancy complications that can improve both maternal and fetal health. For the in-vitro study, we are piloting experiment to confirm DFFOCTs ability to capture metabolically coupled movements in in-vitro samples recorded in RGB scale. We compare the images of cells cultured at physiological hypoxia and hyperoxia with DFFOCT to see the difference in the dynamics and use protein expression to verify the altered cellular metabolism. This involves achieving the oxygenation states by using oxygen-controlled incubator, pre-equilibrating the cell culture media by bubbling oxygen or nitrogen and monitoring with an oxygen probe. Since maintaining a certain oxygen level is easily disturbed when exposed to ambient air, we are passing the pre-equilibrated media over the sample while imaging to keep the desired oxygen level. The measured data will be statistically analyzed to validate the findings. Through this study, we expect to establish understanding of placental metabolism under varied oxygenation states. Facial plethora is one of the earliest described clinical features of Cushings syndrome (CS). In collaboration with SEG at NICHD, we have quantified changes of facial plethora in CS as an early assessment of cure. Non-invasive multi-spectral near-infrared imaging was performed on the right cheek of the patients before and after surgery. Patients were defined as cured by post-operative measurements of plasma cortisol less than 3 (mcg/dl), and/or adrenocortical insufficiency for which they received replacement. Results indicate that a decrease in facial plethora after surgery, as evidenced by decrease in blood volume fraction, is correlated with cure of CS. The first set of results were published in the journal of clinical endocrinology & metabolism. We also showed that water content fraction could be used as a new biomarker of early cure in patients with CS. We ran our methodology for first (3-6 months after surgery, N=22) and second (6 months after the first follow up, N=10) post-surgery follow up, where all subjects are identified clinically in remission state. We are pursuing Kaposi Sarcoma (KS) studies in 3 ongoing NCI clinical trials. Given the capability of our technology, the goal is to further evaluate diffuse multispectral imaging in a relatively large sample as a potential supplement to existing response assessment in KS. In our preliminary results, using multi-spectral imaging, we showed that successful treatment is indicated by decrease the blood volume in the lesions as a quantitative marker of tumor response to therapy. As a next step for our bench to bedside goal, we have developed a new hand-held multispectral camera to be used a point-of-care system. The device uses a high-resolution CMOS camera with on-chip filters. High resolution images (256X256 pixels) are acquired simultaneously at eight different near-infrared wavelengths (700-980 nm). We have also developed a user-friendly graphical interface for data processing in Matlab. Assessment of tumor development in patients can facilitate treatment strategies and early intervention. In our recent published study, we designed time-resolved fluorescence lifetime imaging to distinguish bound Human Epidermal Growth Factor 2 (HER2) specific affibody probes to HER2 receptors in live animals. Our results show that changes in fluorescence lifetime of the bound contrast agent can be used to rapidly assess the high to mid-level expression of HER2 expressing tumors in-vivo. In another study, we aimed to use the PReterm IMaging system based on colposcope to characterize uterine cervix structure in a longitudinal study of low- and high-risk (prior preterm birth (PTB) or a sonographic short cervix) patients. Polarization imaging is an effective tool to measure optical anisotropy in birefringent materials, such as the cervix's extracellular matrix and to predict cervical ripening and potentially to diagnose pre-term birth. We developed a handheld colposcope device for active polarization imaging of the cervix. Through our under-review collaboration with Wayne State Universitys Perinatology Research Branch and Florida International University we will test our system in a control population and those with PTB prevalence.

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