Quantitative Biophotonics for Tissue Characterization and Function

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

Placenta plays a crucial role in both mother and fetal health. Abnormal placenta has been linked to pregnancy complications such as preeclampsia, fetal growth restriction, fetal death, preterm labor, and other complications. 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. However, the results of studies observing the level of oxygenation in the placenta have been conflicting. This discrepancy may be due to the unknown placental reduced scattering coefficient used in oxygenation calculations or to differences in patient populations. 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. Different source and detector distances help scan different tissue depths to differentiate placental and maternal oxygenation. This device also uses two light sources with 760 nm and 840 nm wavelengths because they are sensitive to changes in blood oxyhemoglobin and deoxyhemoglobin. The performance evaluation of the NIRS device was confirmed by observing changes in the optical properties of a placental-mimicking phantom at a depth of 25 mm. In addition, to assess accuracy and validate the performance of the custom-made NIRS device, in-vivo oxygenation measurement was performed in two human subjects at multiple parts of the body including both arms, calves, and abdomen using the wearable NIRS device and a time-domain NIRS system (TRS-41 system, Hamamatsu photonics, Japan). An averaged error of 2.7% 1.8% was found between the two device/system. The agreement between measurements from the wearable NIRS device and a well-established TRS system validates a high accuracy of our device in measuring in-vivo tissue oxygenation. 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). We have performed measurements at 3 different positions: upper, middle, and lower parts of the placenta. Among 12 subjects, five of them had maternal pregnancy complications, including short cervix, hypertension and polyhydramnios. Eleven out of twelve participants delivered at the DMC. After delivery, the placentas of 10 of the 11 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. Placental oxygenation level was calculated using the intensity of backscattered light at appropriate source-detector separations. For each patient, three oxygenation levels at the three measurement sites: the upper, middle, and lower parts of the placenta. When calculating oxygenation level, the placental reduced scattering coefficient calculated from our previous data (_s'(760) = 0.915 mm-1 and _s' (840) = 0.793 mm-1) was used. A two-way ANOVA was used to compare oxygenation levels based on both measurement positions (middle n = 12, upper n = 12, lower n = 12) and maternal complication status (No complication n = 7, with complication n = 5). The result showed a significantly higher oxygenation level in the group with an uncomplicated pregnancy (75.0% 5.8%) compared to those with pregnancy complications (69.4% 6.7%) (F(1,30) = 7.8, p = 0.009). Significant difference in the mean oxygenation levels at the middle (69.1% 6.8%), upper (74.5% 6.3%), and lower (74.3% 5.9%) parts of the placenta (F(2,30) = 3.5, p = 0.044) was further observed. In addition, there was no significant interaction between complication status and measurement positions (F(2,30) = 0.1, p = 0.889). Based on the placental pathology, the tissue oxygenation levels were divided into two groups, placenta-with-lesions and placenta-without-lesions groups. A two-way ANOVA was performed to compare placental oxygenation levels at different measurement positions above the placenta (middle n = 10, upper n = 10, lower n = 10) and presence of placental lesions (no lesion n = 5, with lesions n = 5). The statistical test indicated a significantly lower oxygenation level in those with presence of placental lesions (68.7% 5.6%) group than those without lesions (74.2% 5.8%) group (F(1,24) = 7.7, p = 0.010) across all measurement sites. No significant difference in the mean oxygenation levels at the different measurement sites (F(2,24) = 3.2, p = 0.061) were observed. The interaction between the lesion presence and measurement position was not significant (F(2,24) = 0.2, p = 0.822). 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). We will conduct further study to includes more subjects. DFFOCT: As a parallel experiment with placenta oxygenation measurement using NIRS device, we are developing an analysis algorithm to evaluate the behavior of placental cells considering different oxygenation levels using Dynamic Full-field Optical Coherence Tomography (DFFOCT) system. The algorithm under development is to analyze changes in dynamic activity (frequency and magnitude of cells) within a cell and calculate mean frequency which represents the frequencies with high weights. We conducted experiment to evaluate viability states of the HeLa cells, which is an immortal human cell line widely used in cell research, from alive to death. Cell dynamic activity was quantitatively and clearly differentiated according to changes in viability status. From these results, we believe that DFFOCT can be used to analyze variations of cellular dynamic activity depending on nutrient and oxygen saturation contained in placental cells.. Biosensor Project: The COVID-19 pandemic has challenged the health care community to develop biosensors to detect patients with early signs of a COVID-19 infection. We developed and tested a multimodal sensing device for monitoring parameters associated with physiological changes in respiratory infectious diseases. This device consists of three sensors for Near Infrared Spectroscopy (NIRS), Photoplethysmography (PPG) and temperature sensing. Near infrared spectroscopy is a non-invasive method to obtain blood hemoglobin concentration using near infrared (NIR) light sources. PPG is another optical method that detects blood volume changes at the microvasculature level. Respiratory function and cardiac parameters will be obtained from NIRS and PPG signals, respectively. This devices NIRS sensor uses three-wavelength source (730nm, 810nm and 850nm) with three source-detector distances of 2,3,4cm different from a traditional sensor. The third wavelength and resultant extra depth information is used to obtain tissue oxygenation values, which is a novel, more informative oxygenation parameter added to the wearable biosensor. The final prototype is inexpensive and wireless, with Bluetooth functionality for point-of-care home-accessible purposes. Preliminary data showed a significant change in respiratory parameters detected by the device between normal, healthy breathing and breathing that simulated what is observed in patients with a respiratory infection. In future work, after collecting data from COVID-19 patients, we hope that through using AI and machine learning analysis we can identify a pattern of NIRS specific to COVID-19.