CAREER: Growth and Remodeling of the Uterine Cervix During Pregnancy

这一NSF教师早期职业发展(职业)计划奖将描述导致早产(PTB)的生物力学机制，并将通过面向女性健康的教育活动培训下一代女性工程师。尽管产前护理取得了进步，但美国的肺结核(怀孕37周前出生)的比率仍然很高。这一事实突显了人们对肺结核的病因知之甚少，肺结核是五岁以下儿童死亡的主要原因。研究人员确实知道，宫颈是一个位于子宫底部的圆柱形器官，是维持婴儿足月发育的关键机械屏障。然后，在分娩时，宫颈在荷尔蒙提示的指导下重塑、软化和扩张，成为婴儿的安全通道。如果宫颈组织重塑的时机关闭，PTB可能是由于宫颈过早扩张而发生的。对宫颈重塑过程的了解是有限的，因为目前还没有工程工具来描述正常和异常的宫颈软化。为了满足这一需求，本研究将测量不同激素提示下宫颈的机械和生化特性变化，并推导出一套可以预测怀孕期间宫颈机械功能的方程。这项研究将使人们更好地了解与宫颈功能障碍相关的肺结核的潜在原因，并将是开发合理的治疗方法预防肺结核的关键一步。这项职业研究将为妊娠期间宫颈的生长和重塑提供一个结构性材料模拟框架。主要目标是确定导致宫颈过早重塑和宫颈机械功能障碍的驱动因素。建模框架将基于雌激素和孕激素水平在调节怀孕期间宫颈组织成分方面发挥关键作用的证据。宫颈组织将被模拟为水合纤维复合多孔材料，其中间质孔隙空间允许固体块的生长和去除。相关的材料参数将作为激素介导的细胞外基质成分状态变量的函数而演变。模型功能将基于孕期宫颈组织样本的机械和胶原特征，这些样本来自激素介导的正常、早产和中断的宫颈重塑的已建立的小鼠模型。这些公式将通过评估它们对负荷和荷尔蒙驱动的组织变化的材料反应的预测能力来验证。

This NSF Faculty Early Career Development (CAREER) Program award will characterize the biomechanical mechanisms that cause preterm birth (PTB) and will train the next generation of female engineers with educational activities geared towards Women's Health. Despite advances in prenatal care, the rate of PTB (birth before 37 weeks of gestation) in the United States remains high. This fact underscores how little is known about the causes of PTB, which is a leading cause of death in children under five. Researchers do know that the cervix, a cylindrical organ located at the base of the uterus, is a critical mechanical barrier to maintain the baby to full term. Then, at time of delivery the cervix is instructed by hormonal cues to remodel, soften, and dilate to become a safe passage for the baby. If this cervical tissue remodeling timing is off, PTB can occur due to premature cervical dilation. The understanding of this cervical remodeling process is limited because there are no engineering tools to characterize normal and abnormal cervical softening. To address this need, this study will measure the mechanical and biochemical property changes of the cervix under various hormonal cues and derive a set of equations that can predict the mechanical function of the cervix during pregnancy. This study will bring an improved understanding to the underlying causes of PTB related to cervical dysfunction, and will be an essential step toward the development of rational therapies to prevent PTB.This CAREER study will derive a constitutive material modeling framework for the growth and remodeling of the cervix during pregnancy. The main goal is to determine the driving factors that cause premature cervical remodeling and the mechanical dysfunction of the cervix. The modeling framework will be based on the evidence that levels of estrogen and progesterone play a key role in regulating cervical tissue composition during pregnancy. Cervical tissue will be modeled as a hydrated fiber composite porous material where the interstitial pore space allows for the growth and removal of solid mass. The associated material parameters will evolve as a function of hormone-mediated extracelluar matrix compositional state variables. Model functions will be based on mechanical and collagen characterization of gestation-timed cervical tissue samples taken from established mouse models of hormone-mediated normal, preterm, and disrupted cervical remodeling. These equations will be validated by assessing their predictive capability of the material response to loading and hormonally-driven tissue changes.