A Multi-Modality, Multi-Scale Approach to Understanding Parturition

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Project Summary The U.S. preterm birth rate is increasing 1 and it estimated that if all pregnant women were screened and offered appropriate available intervention, 95% of PTB would still occur, 2 which both indicates that we have exhausted all currently available options and reflects our poor understanding of the molecular mechanisms underlying this complex and common problem that affects every society in the world. Recent findings from our labs challenge the existing paradigm of cervical remodeling in pregnancy. They suggest that perhaps ripening just prior to delivery is not a simple acceleration or enhancement of the softening that occurs progressively from just after conception through delivery, but rather is driven by entirely different mechanisms, perhaps by minor ECM components and/or non-ECM components, some of which are likely still unidentified. We have come to suspect that the collagen in the ECM reaches a point after which it rearranges no further, despite continued cervical softening and loss of strength, and that non-ECM components (e.g. blood vessels) play a significant role. These findings hint at a compelling alternative paradigm for cervical remodeling, but even more, they reveal a large knowledge gap in our understanding of parturition in general. Our goal is to address this gap, and explore this potential new paradigm, by constructing patient-specific biomechanical models that delineate the structure-function relationship of the cervix and other tissues that support the fetus (membranes, uterus), based on specific measurements of cervical microstructure and maternal anatomy in each individual. We will also explore the contribution of potential minor extracellular matrix (ECM) and non-ECM informants of cervical remodeling. To this end, we will use our Rhesus macaque model to longitudinally measure in vivo tissue microstructural properties and maternal anatomy throughout pregnancy using ultrasound, formulate and validate relationships between ultrasound parameters and tissue material properties for the cervix in ex vivo gestation-timed samples, explore relationships between tissue biochemical composition and material properties for the cervix, uterus, and fetal membranes using the ex vivo samples, and calculate the precise magnitude and regional distribution of tissue stress and stretch for each macaque using finite element analysis directly informed by her individual microstructural tissue and anatomical properties. The fundamental model will be flexible enough to eventually accommodate other potential contributors to cervical remodeling, such as minor ECM factors, or non-ECM factors. To this end, we will build upon the successes of our current R01 by expanding our Rhesus model to deeply explore the relationship between cervical microstructure and maternal anatomy, and search for correlations between biomechanical properties of the cervix and potential influences on cervical remodeling of minor ECM, and non-ECM, components. Ultimately, we envision a modeling tool that incorporates both imaging and biological biomarkers for a comprehensive picture of an individual's pregnancy, which will allow prediction of birth timing, and could even expose therapeutic targets for abnormal (preterm or postdates) timing.