Characterizing the structure-function relationships of the mouse cervix in pregnancy
The timely remodeling of the cervix from a mechanical barrier into a soft, compliant structure, which dilates in response to uterine contractions is crucial for the safe delivery for a term baby. A cervix which softens too early in the pregnancy is implicated in spontaneous preterm births (sPTB). Currently, 15 million babies are affected by PTB annually, early diagnosis is difficult, and 95% of all PTBs are unmanageable by available therapies. These statistics highlight the need to better understand the biological processes involved in cervical remodeling and its downstream effects on material properties. To address this need, we propose the development of a hormone-mediated material constitutive model for the cervix where steroid hormone actions on key tissue constituents are incorporated into a microstructure-inspired material model. As the first steps towards the development of this model, the main objective of this dissertation work is to understand the key structure-mechanical function relationships involved in pregnancy. To understand cervical material property changes, the equilibrium swelling and tensile response of the nonpregnant and pregnant mouse cervix is measured, a porous fiber composite material model is proposed, and the model is fit to the mechanical data then validated. To better understand key tissue constituents involved, the evolution of intermolecular collagen crosslinks is determined in normal pregnancy and the role of the small proteoglycan, decorin, and elastic fiber structure on cervical mechanical function is investigated. The results presented here demonstrate that a porous, continuously distributed fiber composite model captures the three-dimensional mechanical properties of the nonpregnant and pregnant cervix. The material property changes of the cervix in a 19-day mouse gestation is described as a four order of magnitude decrease in the parameter associated with the fiber stiffness. We provide quantitative evidence to demonstrate the role of collagen crosslinks on tissue softening in the first 15 days, but not in the latter stages of a mouse pregnancy. A role of elastic fiber structure on cervical mechanical function is demonstrated, as well as distinct roles of estrogen on elastic fiber structure and progesterone on collagen fibril structure. Lastly, an analysis of the time-dependent response of cervices from nonpregnant, normal pregnant, and induced PTB mice are presented. This dissertation concludes by reviewing the presented data within the context of the proposed framework to suggest future directions towards its development.
