Quantitative Biophotonics for Tissue Characterization and Function

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

Investigators

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Abstract

Observing the placenta offers a look into the in utero fetal environment. Variations in the size of the placenta throughout early pregnancy have been associated with placental injury from factors such as maternal malnutrition or anemia. Reduced uteroplacental perfusion is often associated with fetal growth restriction (FGR), a condition where the fetus fails to reach their genetic growth potential, and the associated condition, pre-eclampsia. In cases of pre-eclampsia, pregnant women will often have hypertension, protein in their urine, and symptoms such as blurred vision and headaches, posing significant health risks to the mother. Additionally, pre-eclampsia and fetal growth restriction can increase risk for perinatal death of the fetus and premature delivery. Reduced uteroplacental perfusion can also lead to chronic hypoxia, a condition where the tissue is not oxygenated adequately, and poor fetal nutrition. These factors increase risk for cognitive impairments in the child, including cerebral palsy and lifelong metabolic outcomes. Additionally, reduced perfusion can lead to perinatal asphyxia, a lack of oxygen and blood flow to the fetus before, during, or immediately after birth. More severe cases of asphyxia, where the fetus has low oxygen levels for an extended period, may result in permanent damage to the babys major organs, including the brain, liver, and kidneys, or organ failure and death. Therefore, monitoring placental oxygenation may be useful in distinguishing between a normal fetus and one with FGR and/or associated conditions and might predict pregnancy outcome. Additionally, identification of such complications during pregnancy can allow for earlier interventions, including medications to reduce risk of perinatal mortality (e.g., sildenafil, esomeprazole, and metformin) and maternal gene therapy. While research on these interventions is still in its infancy, identifying pregnancy complications prior to birth may allow mothers and their physicians to take necessary precautions. Near-infrared spectroscopy (NIRS) is an optical method for the non-invasive measurement of blood oxygenated and deoxygenated hemoglobin and tissue oxygenation in deep tissue layers such as the brain, muscle, and placenta. A major challenge in the assessment of placental oxygenation using NIRS arises from the anatomical location of the organ. Taking into account the anatomical location of the maternal placenta (e.g. skin, adipose tissue, uterine wall), a novel wearable depth-resolved NIRS device featuring six source-detector distances ranging from 10-60 mm has been designed to scope different tissue layers. The performance evaluation of the NIRS device was confirmed and validated in two human subjects at multiple parts of the body including both arms, calves, and abdomen with a commercial time-domain NIRS system (TRS-41 system, Hamamatsu photonics, Japan). An averaged error of 2.7% was found between the two device/system. The NIRS device was then used to measure in-vivo placental oxygenation in 12 volunteer subjects at the Center for Advanced Obstetrical Care and Research of the Perinatology Research Branch, located at the Detroit Medical Center (DMC, Detroit, Michigan, USA) (Nguyen et. al, 2021). Among 12 subjects, five of them had maternal pregnancy complications, including short cervix, hypertension and polyhydramnios. After delivery, the placentas of 10 participants were delivered to the pathology department at the DMC to inspect for lesions. Five placentas were found to have chronic or acute lesions, four of which belonged to participants with maternal pregnancy complications. The result showed a significantly higher oxygenation level in the group with an uncomplicated pregnancy compared to those with pregnancy complications. Additionally, significantly lower oxygenation level was observed in those with presence of placental lesions group than those without lesions. Our results suggest the possibility of the relationship between the placental oxygenation level and pregnancy complications and placental pathology. However, the sample size used in this study is small (12 participants) and the placental oxygenation level was only measured in the third trimester. We are now developing a clinical protocol to measure placental oxygenation level in a large population (targeting 1000 pregnant women) of both healthy pregnancy and pregnancy with various underlined complications. Placental oxygenation level will be measured from 20 weeks of pregnancy until delivery in every prenatal care visit. On the other hand, we are upgrading our NIRS device by adding motion sensors to monitor fetal movement. Placental oxygenation level and fetal movement will be used to predict the fetal well-being.In a parallel study with the effect of placental oxygenation on the fetus using the NIRS device, we are developing an algorithm to evaluate the metabolism of placental cells according to oxygen levels using the Dynamic Full-field Optical Coherence Tomography (DFFOCT) system. We verified with HeLa cells similar to Placenta cells that the metabolism of cells can be analyzed by dynamic activity (frequency and magnitude of cells) within a cell and calculate mean frequency which represents the frequencies with high weights. A technology is needed to efficiently distinguish the irregular dynamic activity obtained from numerous cells. As a prior algorithm development, we developed an analysis method for cell death evaluation using four well-known supervised machine learning models on dynamic activity data and an average balanced accuracy of 93.92 0.86% using four well know machine learning models (Logistic Regression, Random Forest, Support vector machine, Gaussian Nave Bayes) (Park et. al, 2022). In the future, we plan to apply this technology to the observation of dynamic activity changes according to oxygen saturation of placenta cells and study the fetus. The worldwide outbreak of novel Coronavirus Disease (COVID-19) has created a massive challenge for researchers and health professionals to increase testing capabilities and alleviate stress on the healthcare system. New tools are needed for diagnostic testing and monitoring under-treatment/observation patients who are infected by the virus. Many commercial wearable devices including the Apple Watch, Fitbit, and Oura ring are all currently being studied for potential use in detecting early signs of viral infection. However, these devices do not assess oxygenation. Low oxygen saturation is an important parameter to consider for respiratory illness. Although pulse oximetry is commonly used to measure arterial tissue oxygenation, NIRS can capture oxygenation from the arteries, veins, capillaries and blood vessels, and is more sensitive to tissue perfusion. We developed a multimodal biosensor device for monitoring parameters associated with physiological changes in respiratory infectious diseases. This device consists of three sensors for Near Infrared Spectroscopy (NIRS), motion and temperature sensing, which can measure tissue oxygenation, body temperature, respiratory functions, and cardiac parameters. The device is being validated over commercial devices in a clinical protocol involving healthy volunteers. The protocol simulates different breathing patterns through a breath holding, a paced breathing, and a hypercapnia task. Preliminary data on fours participant have shown that physiological parameters measured from biosensors devices are consistent with the parameters measured with a commercial device. Change in tissue oxygenation was observed during a stimulated breathing task compared to resting state. However, data needed to be collected on more participants to draw a statistical conclusion. In future work, we are planning to derive a general index that can be used as an indicator of COVID-19 patient well-being.