Session: 16-01-01: Government Agency Student Poster Competition

Paper Number: 149660

149660 - Computational Investigation of Uterine Adaptation and Mechanical Function During Pregnancy 

Introduction:

The uterus is a muscular organ that deforms significantly during pregnancy, facilitated through extensive growth and remodeling. Abnormal growth and remodeling are implicated in compromised mechanical function. In soft tissues, cells respond to and tune their mechanical environment by growing/proliferating, remodeling their extracellular matrix, and changing in contractility. However, the mechanical cues driving these functions in the uterus are unclear and difficult to isolate experimentally. Computational modeling can decouple growth, stretch, and remodeling, allowing us to probe how these adaptations change the uterine mechanical environment and thus impact contractile function. Extensive data on mouse pregnancy are available to inform computational models. Therefore, the purpose of this research is to quantify the effects of uterine growth and remodeling on the mechanical environment (elastic stretch and passive stress) and mechanical function (active stress/contractility) of the pregnant murine uterus, using computational modeling. This model provides insight into mechanical cues that may be implicated in preterm birth.

 

Contributions:

Preterm birth (PTB), birth before 37 weeks, is a serious and prevalent condition, affecting millions – particularly disadvantaged and minority groups. PTB is the leading cause of newborn mortality in the U.S., but we lack a basic understanding of its underlying mechanisms. One avenue is a premature increase in uterine contractility, which may be driven by abnormal growth and remodeling. Here, we apply engineering tools to biology by building the first computational model to simulate growth and remodeling in the pregnant mouse uterus. By accounting for in vivo loading conditions, this model provides an advanced understanding of the in vivo mechanical environment and a better prediction of contractile function than predictions from ex vivo data. Our results inform how we can better think about treating and preventing PTB.

 

Methodology:

We built a finite element model of the nonpregnant mouse uterus with parameters informed by experimental data. Geometry was based on gross measurements of a nonpregnant uterus. The model included longitudinal and circumferential fiber layers to mimic the known uterine structure. Pregnancy was simulated by prescribing size change of “pups” based on geometry measurements of pup growth throughout gestation. We assumed constant tissue density and fit a uterine tissue growth equation to uterine weight data. Growth was input as a change in the Jacobian of the tissue in the fiber direction. Using the kinematic growth framework, the total deformation of the uterus was defined as a product of elastic deformation and growth deformation. A constitutive material model was fit to passive stretch-stress data at each gestation timepoint. Active contraction was prescribed according to experimental stretch-active stress curves at each timepoint. To understand how growth and remodeling affect elastic stretch, passive stress, and active stress, we varied the amounts of growth and/or remodeling at 5 timepoints during a 19-day gestation.

 

Preliminary results and conclusions:

The simulation without adaptation showed an increasing elastic stretch throughout gestation, from 1.32[-] at day 7 (d7) to 2.93[-] by d19, while passive stress increased from 1.27-9.46[mN/mm^2] between d7-19 and active stress increased from 5.54-15.12[mN/mm^2]. When growth was included, elastic stretch remained around 1.29[-] from d7-d17, increasing to 1.82[-] at d19. Similarly, passive stress remained around 1.17[mN/mm^2] until increasing to 2.67[mN/mm^2] at d19. Active stress increased from 5.04-10.68[mN/mm^2] at d19, a 29% reduction of the maximum compared to the no-adaptation case. In the remodeling case, elastic stretch values matched the no-adaptation case. The passive stress, however, remained low (~0.83[mN/mm^2]) until d19 (2.03[mN/mm^2]). When the model accounted for both growth and remodeling, elastic stretch values matched the growth case. Passive stress remained low (~0.72[mN/mm^2]) at all timepoints. Active stress increased from 4.95-10.65[mN/mm^2] between d7-19, the same maximum as the growth case and significantly reduced from cases without growth. In conclusion, our analysis suggests that the uterus grows to maintain a constant elastic stretch and remodels to maintain a constant passive stress. Additionally, we demonstrate the importance of growth in reducing uterine active stress until delivery, potentially reducing the risk of PTB.

Presenting Author: Emily Hoffmann University of Minnesota

Presenting Author Biography: Emily Hoffmann is a Ph.D. candidate and NSF Graduate Research Fellow in the Department of Biomedical Engineering at the University of Minnesota. She received her B.S. in Biomedical Engineering and a B.S. in Mechanical Engineering at Colorado State University. Her research centers on uterine biomechanical adaptations during pregnancy. Specifically, she uses experimental techniques and computational modeling to understand how adaptations on the cell- and tissue-scale interact to support a healthy gestation and delivery.

Authors:

Emily Hoffmann University of Minnesota
Kyoko Yoshida University of Minnesota