Monitoring the placenta oxygenation and vascular network binding the expectant mother to the fetus is critical to ensure a healthy pregnancy outcome. Reduced uteroplacental perfusion has been associated with preeclampsia and intrauterine growth restriction and reduced oxygenation can lead to fetal hypoxia, asphyxia, and cerebral palsy. However, there are instances that higher oxygenation at the intervillous space during pregnancy has been associated with abnormal placental function. On the other hand, there are no patient-friendly devices to measure the oxygenation of the placenta. Therefore, it is crucial to have a quantitative understanding of placental oxygenation to detect any abnormality (i.e. increase or decrease) compared to normal placental function. Functional Near Infrared Spectroscopy (fNIRS) provides a technique that can address these challenges with its wearable, wireless capability that is convenient for dynamic monitoring. We intend to 1) find the baseline for the normal vs abnormal pregnancies and to standardize the oxygenation data across pregnancies and 2) correlate the oxygenation data with the pregnancy outcomes. We have accomplished the first critical phase of this project at the bench. We now have a fast, non-invasive and wearable device with wireless capability to allow continuous measurement of the oxygenation of the anterior placenta in a subject-friendly environment. This compact system, only weighting 1.4 ounces can be positioned at different abdominal locations for efficient and localized measurement of oxygenation. In detail the device consists of two detectors and 3 sources. Since the probing depth of NIRS depends on the source detector separation, we have devised the system to interrogate at different depth. This would provide us with information regarding different tissue types and to distinguish between maternal and placental tissue. The NIRS device uses the light in near infrared region at two wavelengths (760 and 850 nm) that are sensitive to changes in oxy-hemoglobin and deoxy-hemoglobin. The light enters the tissue at the location of source and the back scattered light will be detected at the detector site. The light intensities are within FDA requirements, Class I devices (<100 mW), for patient safety. The multiple source-detector design will allow probing different vascular compartments of the womb. By adding frequency filtering related to the pulsation of the maternal tissue we expect to separate the hemodynamics of the placenta from maternal tissue. Using similar approach, we were able to create a new index, oxygenation variability index (OVI), which is correlated to the cerebral autoregulation in brain. This index can be seen as the coefficient of variation of instantaneous oxygen saturation in frequency band directly related to the blood autoregulation. The pertinence of this quantitative parameter has been tested in for brain activation in children (age 4-8) 4. We have tested the performance of the device on the static phantom that mimics the optical properties of the uterus and placenta tissue. Using the device we were able to distinguish between the layers and interrogate at different depth level. Our general strategy is to monitor the oxygenation of placenta dynamically. Therefore we propose to use the state of the art 3D printing to simulate a dynamic placenta model. The 3D model will mimic both structural and functional aspect of the placenta and maternal tissue and provides more in depth analysis of the NIRS signal regarding the changes in oxygenation of the placenta. Dr. Shad Deering at USUHS will guide us through this collaboration as we expect to test our device through a pilot study.
The aim i s to find a baseline of placenta oxygenation in normal pregnancy. One challenge is the ability to separate maternal tissue oxygenation from placental oxygenation. This involves refining our data analysis software by incorporating anatomical localization and to standardized it across pregnancy. The outcome may be to provide earlier detection of pregnancy complications that can improve both maternal and fetal health. Facial plethora is one of the earliest described clinical features of Cushings syndrome (CS). In collaboration with NICHD (Dr. Stratakis group), we have continued the study aimed at quantifying changes of facial plethora in CS as an early assessment of cure. Cushings patients are recruited for optical imaging, before and after surgery with follow-up sessions at 6 months and 2 years after surgery. To date, we have been able to reconstruct biological parameters of 61 subjects. Non-invasive multi-spectral near-infrared imaging was performed on the right cheek of the patient before and 2 days or up to 2 weeks 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. Clinical data, obtained from 57 patients, indicate that a decrease in facial plethora after surgery, as evidenced by decrease in blood volume fraction, is well correlated with cure of CS. The first set of results were published in the journal of clinical endocrinology & metabolism (JCEM). We recently explored the same trend by water content fraction. Findings show water content fraction could also quantify facial plethora as a new biomarker of early cure in patients with CS. We observed that a fraction of the cheeks water content, measured by the multi-spectral system, could be used to differentiate cured and non-cured CS patients within a short time after surgical treatment. The findings for both blood volume and water content fractions have correlated significantly, but it seems blood volume is relatively better associated with clinical evaluations. A number of false-negatives in water content analysis are slightly more. We ran our methodology and analytic algorithm for first and second post-surgery follow up. The first follow up usually occurs 3 to 6 months after surgery and second 6 months after the first follow up. We have processed data for 22 imaged patients from their first follow up and ten in their second follow up. So far, all have been identified clinically in remission state by their last visit. The results confirmed our hypothesis that patients, who were assessed as cured, based on significant drop in their cortisol level after the surgery, kept a smaller blood volume fraction in the region of interest (ROI) versus before surgical treatment in the follow up sessions as well. We are pursuing Kaposi Sarcoma (KS) studies in 4 ongoing NCI clinical trials. After processing more patients under a new classification with results of supporting proof for the capability of our novel technology as a robust device, the goal is to further evaluate diffuse multispectral imaging in a relatively large sample as a potential supplement to existing response assessment in KS, providing an early non-invasive marker of treatment efficacy. In our preliminary results, multi-spectral images of Kaposi Sarcoma skin lesions were taken over the course of treatment, and blood volume and oxygenation concentration maps were obtained through Principal Component Analysis (PCA) of the data. Corresponding images were compared with clinical and pathological assessment, provided by conventional means. In agreement with our hypothesis that successful treatment would decrease the blood volume in the lesions, the normalized standard deviation for blood volume decreased in each of the eight patients whose lesion responded to treatment, while the normalized standard deviation for blood volume increased in two patients whose lesion did not respond to therapy. These initial results confirm that concentrations of oxygenated hemoglobin in the tumor can become a quantitative marker of tumor response to therapy.

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