1. Fetal Cardiac Examination Using Fetal Intelligent Navigation Echocardiography (FINE):Congenital heart disease is the most common group of malformations affecting both fetuses and newborn infants. Up to 90% of cases of cardiac defects occur in pregnancies without high risk features. Therefore, this provides the impetus to perform a comprehensive screening examination of the fetal heart in all women to maximize the detection of heart defects. Yet, even when more than 90% of women in the population undergo a prenatal ultrasound examination, studies report a low sensitivity (22.5% 52.8%) in the detection of congenital heart disease. This has been attributed mainly to operator expertise and experience. Some of the limitations of conventional two-dimensional ultrasound could be resolved by technological advances designed to reduce operator-dependency. Four-dimensional sonography with spatiotemporal image correlation (STIC) allows acquisition of volume datasets of the fetal heart, and displays a cine loop of a complete single cardiac cycle in motion. Such sonographic volumes allow cardiac planes to be extracted and displayed in any orientation. Yet, this process requires an in-depth knowledge of anatomy, and is difficult, operator-dependent, and time consuming. Recently, we developed and reported a novel method known as Fetal Intelligent Navigation Echocardiography (FINE), which interrogates STIC volume datasets using intelligent navigation technology. This allows the automatic display of nine standard fetal echocardiography views required to diagnose most cardiac defects. Such method can simplify examination of the fetal heart and reduce operator dependency. This year, we conducted a study to prospectively evaluate the performance of the FINE method applied to STIC volume datasets of the normal fetal heart acquired between 19 and 30 weeks of gestation. One or more STIC volumes were successfully obtained in 72.5% (150/207) of women undergoing ultrasound examination. Approximately 96% (n=351) of STIC volumes evaluated by STICLoop were determined to be appropriate. Nine fetal echocardiography views were generated by the FINE method using a combination of diagnostic planes and/or VIS-Assistance in 98-100% of cases. For each STIC volume dataset, 86% of volumes demonstrated either 8 or all 9 echocardiography views (via diagnostic planes), while 98% of volumes demonstrated all 9 echocardiography views (via VIS-Assistance). For each STIC volume dataset, the success rate of obtaining four views (four chamber, left ventricular outflow tract, short-axis view of great vessels/right ventricular outflow tract, abdomen/stomach) was 93% and 100%, using diagnostic planes and VIS-Assistance, respectively. Therefore, such findings suggest that FINE could be implemented in fetal cardiac screening programs. 2. Elastography to Assess Biophysical Properties of the Human Cervix and the Risk of Preterm Delivery: Throughout gestation, the cervix undergoes dynamic changes in tissue composition characterized by dynamic remodeling of the collagen network and an increased concentration of glycosaminoglycans and water content in the extracellular matrix. Elastography is a sonographic technique for estimating tissue displacement or deformation when oscillatory compression is applied. Tissue displacement or strain can be tracked using Doppler techniques or cross-correlation analysis, and converted to an elastic modulus as an indirect estimation of tissue stiffness. Currently, identification of a short cervix by transvaginal ultrasound is the most powerful predictor for spontaneous preterm delivery. However, there is a need to determine the value of elastography in women who will present with preterm delivery, and whether any associations are altered by the presence of a short cervix. We used quasi-static elastography to estimate cervical strain in 545 pregnant women with singleton gestations from 11 to 28 weeks of gestation. Cervical strain was evaluated in one sagittal plane, and in cross-sectional planes of both the internal cervical os and external cervical os. Women with strain values in the 3rd or 4th quartiles at the internal cervical os had an increased risk of spontaneous preterm delivery at ≤34 weeks and <37 weeks of gestation compared to women with the lowest quartile strain values. Even after adjusting for gestational age and a short cervix, women with strain values in the 3rd quartile maintained a significantly elevated risk for spontaneous preterm delivery, while those with highest quartile strain values had a marginally increased risk (relative to women with lowest quartile strain values). This is the first study describing the association between cervical strain and preterm delivery at ≤34 weeks and magnitudes of association between cervical strain and preterm delivery adjusted for both gestational age at examination and the presence of a short cervix. Thus, this report lays the groundwork for further investigation on the clinical benefit of elastography in combination with cervical length measurement to identify women at risk for spontaneous preterm delivery. 3. Development of Placenta-on-a-Chip a Novel Platform to Study Biology of the Human Placenta: The most important function of the placenta is the exchange of endogenous and exogenous substances, which enable an adequate supply of oxygen and nutrients, excretion of fetal metabolic waste, and protection against potentially harmful agents, such as xenobiotics, bacteria, viruses, and parasites. Prior studies on placental transport have used a wide range of experimental systems, including in-vivo animal models, ex-vivo placental perfusion systems, and in-vitro cell cultures. In some cases, placental transfer has been studied in humans for frequently used therapeutic agents, such as antibiotics and hormones. However, such studies are difficult to perform, time-consuming, and always carry the risk of fetal exposure. This year, we proposed a new bioengineering approach to model placental transport that combines microfluidics and microfabrication technologies with the culture of placenta-derived human cells to recapitulate the organ-specific architecture and physiological microenvironment critical to placental barrier function. Specifically, we developed a Placenta-on-a-Chip microdevice that enabled the compartmentalized perfusion co-culture of human trophoblasts (JEG-3) and human umbilical vein endothelial cells (HUVECs) on a thin extracellular matrix membrane (ECM) to create a physiological placental barrier in-vitro. We also tested the physiological function of the microengineered placental barrier by measuring glucose transport across the trophoblast-endothelial interface over time. Our microfluidic cell culture system provided a tightly controlled fluidic environment conducive to the proliferation and maintenance of JEG-3 trophoblasts and HUVECs on the ECM scaffold. Prolonged culture in this model produced confluent cellular monolayers on the intervening membrane that together formed the placental barrier. This in vivo-like microarchitecture was also critical for creating a physiologically relevant effective barrier to glucose transport. Our Placenta-on-a-Chip model has the potential to serve as a low-cost experimental platform with a broad range of applications. This biomimetic model may also enable the quantitative analysis of placental transport of small molecules and biologics for the development and screening of new therapeutic modalities. Finally, the microengineering approach demonstrated in this study could be leveraged to recapitulate key pathological features of different placental disorders to develop new types of in-vitro human disease models.
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