The U.S. preterm birth rate is increasing1 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 re?ects our poor understanding of the molecular mechanisms underlying this complex and common problem that affects every society in the world. Recent ?ndings 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 unidenti?ed. 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 signi?cant role. These ?ndings 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-speci?c biomechanical models that delineate the structure-function relationship of the cervix and other tissues that support the fetus (membranes, uterus), based on speci?c 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 ?nite element analysis directly informed by her individual microstructural tissue and anatomical properties. The fundamental model will be ?exible 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 in?uences 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.

Public Health Relevance

The U.S. preterm birth rate is increasing1 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 re?ects our poor understanding of the molecular mechanisms underlying this complex problem that affects every aspect of every society in the world. This proposal addresses our enormous knowledge gap surrounding pregnancy and delivery by taking advantage of the quantitative ultrasound technology we have developed for objective quanti?cation of the microstructural changes (collagen organization and cervical softness) in our Rhesus macaque model of pregnancy to construct patient-speci?c biomechanical models that are informed by precise imaging biomarkers (measurements of not only an individual's cervical microstructure, but also her cervical and uterine anatomy). This personalized modeling tool will be designed to easily accommodate additional relevant biomarkers (e.g. from blood or cervical secretions) as future research develops.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD072077-06
Application #
9524489
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Ilekis, John V
Project Start
2013-01-15
Project End
2023-06-30
Budget Start
2018-09-01
Budget End
2019-06-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Physics
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Rosado-Mendez, Ivan M; Carlson, Lindsey C; Woo, Kaitlin M et al. (2018) Quantitative assessment of cervical softening during pregnancy in the Rhesus macaque with shear wave elasticity imaging. Phys Med Biol 63:085016
Vajihi, Zara; Rosado-Mendez, Ivan M; Hall, Timothy J et al. (2018) Low Variance Estimation of Backscatter Quantitative Ultrasound Parameters Using Dynamic Programming. IEEE Trans Ultrason Ferroelectr Freq Control 65:2042-2053
Guerrero, Quinton W; Fan, Liexiang; Brunke, Shelby et al. (2018) Power Spectrum Consistency among Systems and Transducers. Ultrasound Med Biol 44:2358-2370
Carlson, Lindsey C; Hall, Timothy J; Rosado-Mendez, Ivan M et al. (2018) Detection of Changes in Cervical Softness Using Shear Wave Speed in Early versus Late Pregnancy: An in Vivo Cross-Sectional Study. Ultrasound Med Biol 44:515-521
Guerrero, Quinton W; Feltovich, Helen; Rosado-Mendez, Ivan M et al. (2018) Anisotropy and Spatial Heterogeneity in Quantitative Ultrasound Parameters: Relevance to the Study of the Human Cervix. Ultrasound Med Biol 44:1493-1503
Guerrero, Quinton W; Feltovich, Helen; Rosado-Mendez, Ivan M et al. (2018) Quantitative Ultrasound Biomarkers Based on Backscattered Acoustic Power: Potential for Quantifying Remodeling of the Human Cervix during Pregnancy. Ultrasound Med Biol :
Tyagi, Mohit; Wang, Yuqi; Hall, Timothy J et al. (2017) Improving three-dimensional mechanical imaging of breast lesions with principal component analysis. Med Phys 44:4194-4203
Feltovich, Helen (2017) Cervical Evaluation: From Ancient Medicine to Precision Medicine. Obstet Gynecol 130:51-63
Guerrero, Quinton W; Rosado-Mendez, Ivan M; Drehfal, Lindsey C et al. (2017) Quantifying Backscatter Anisotropy Using the Reference Phantom Method. IEEE Trans Ultrason Ferroelectr Freq Control 64:1063-1077
Rosado-Mendez, Ivan M; Palmeri, Mark L; Drehfal, Lindsey C et al. (2017) Assessment of Structural Heterogeneity and Viscosity in the Cervix Using Shear Wave Elasticity Imaging: Initial Results from a Rhesus Macaque Model. Ultrasound Med Biol 43:790-803

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