published_or_final_version / abstract / toc / Biochemistry / Doctoral / Doctor of Philosophy

Includes bibliographical references (leaves 68-76) Aims to observe changes in the expression of syndecan-1 in both the developing epithelium of the rat oral mucosa, and in epithelial cell rests of Malassez in the developing periodontium of normal rat molars, from late crown development through to early eruption.

Graduation date: 1993

The mechanical function of the uterine cervix is critical for a healthy pregnancy. During pregnancy, the cervix undergoes a significant remodeling from a mechanical barrier into a compliant structure to allow for a successful delivery. A too early or too late cervical softening will lead to spontaneous preterm births (sPTB) or dystocia. PTB is a leading cause of neonatal death, affecting 15 million newly born babies each year around the world. According to CDC, the rate of PTB increases in recent years. Dystocia increases the risk to both mother and newborn babies, leading to neonatal asphyxia, neonatal infection, uterine rupture, or other dangerous sequelae. Therefore, it is significant to have a better correlation of the mechanical properties change and the biological remodeling process of the cervix during pregnancy. This thesis will focus on (1) mechanical experiments of the human cervix, and (2) the development of a material constitutive model for cervix to characterize the complex microstructure-related mechanical property of the cervix. In this thesis, a spherical indentation test was designed and conducted on human cervical samples sliced perpendicular to the axial direction, to characterize the compressive mechanical behavior of the human cervix. A uniaxial tensile was designed and conducted on the strip samples cut along and perpendicular to the preferential fiber direction from the indentation samples, to characterize the tensile mechanical behavior of the cervix. Based on the detailed experimental investigation, a nonlinear time-dependent anisotropic microstructure-inspired constitutive model has been developed. The basic idea of the model is that the mechanical behavior of the human cervix can be decomposed into an equilibrium and a time-dependent part, and the tension and compression mechanical behaviors are caused by disparate mechanisms. Specifically, the collagen fibrous network plays a major role in the tensile mechanical response, while proteoglycans (PGs), glycosaminoglycans (PGs),, and liquid cause the compressive mechanical response. The tensile time-dependent mechanical behavior of the human cervix is mostly attributed to the interactions between the collagen fiber and other components, while the compressive time-dependent mechanical behavior is mainly attributed to the porous effect. The equilibrium and time-dependent mechanical responses have been well captured using the model, and the results reveal the connection between the ECM microstructure remodeling and mechanical properties change during pregnancy.

Preterm birth (PTB), defined as birth before 37 weeks of gestation, is the leading cause of neonatal morbidity, and survivors can face lifelong medical difficulties. PTB remains a clinical challenge worldwide, with rates of PTB rising in all countries with reliable data. A lack in understanding of the mechanisms that lead to PTB has made developing diagnostics and therapeutics challenging, and existing ones are often ineffective. For a successful pregnancy, the major reproductive organs and surrounding tissues must sustain the growing loads of pregnancy. The cervix is one of these major reproductive organs. The cervix sits at the base of the uterus and has a versatile mechanical function in pregnancy. First, it must stay closed during gestation while the fetus develops; second, the cervix must remodel sufficiently and timely to dilate and allow delivery. The proper timing and extent of remodeling are critical for a healthy pregnancy. Improper cervical remodeling is a final common pathway to PTB and is the tissue of focus in this thesis. To improve our ability to identify when a PTB birth will occur and ultimately be able to treat those at risk, this thesis will identify the mechanical role of three extracellular matrix (ECM) components at various gestational ages and evaluate the ability of two major hormones to alter cervix function. Using experimental techniques (large-deformation tensile testing, digital-image correlation, imaging, biochemical) and theoretical and computational techniques (constitutive modeling, finite element analysis), the mechanical behavior of whole mouse cervices will be characterized in wild type, genetic knockout, and hormone-treated animals. First, the loss of both Class-I small leucine rich proteoglycans (SLRPs), decorin and biglycan, is detrimental to cervix function in late gestation. When the cervix should be most compliant and extensible, cervices without decorin and biglycan cannot stretch and are as stiff as the nonpregnant cervix. The loss of these proteoglycans also slows the cervix’s stress dissipation mechanism in late gestation, which could put the cervix at increased risk for damage. The mechanism of stiffening and lost viscoelasticity indicates the fibril crosslinking associated with SLRPs is a structural mechanism of the ECM contributing to cervical remodeling. Second, the loss of hyaluronic acid diminishes the cervix’s mechanical function at every gestational age tested. For nonpregnant to mid-gestational age, the cervix is softer than normal. Though by late gestation, the loss of hyaluronic acid stiffens the cervix; this is at a point when the cervix should be at its softest. The loss of hyaluronic acid also decreases the cervix’s protective stress dissipation mechanism in late gestation. There is limited knowledge of the interaction of collagen, elastic fibers, and hyaluronic acid in the cervix. The significant mechanical role of hyaluronic acid in the cervix warrants exploration of the structural mechanisms of these functional changes. Third, the loss of endogenous hormones stiffens the tissue and increases extensibility compared to the nonpregnant cervix. The administration of estrogen recovers large amounts of extensibility (beyond the stretch level of a late gestation cervix), stiffens the tissue (such that it is stiffer than a nonpregnant cervix), and recovers a significant amount of cervix strength. Fourth, relaxin increases cervix extensibility in mid-gestation and endows the cervix with viscoelastic ability in late gestation. Altogether, understanding the correlation between these extracellular matrix components, hormones, and functional changes of the cervix is fundamental to teasing out mechanisms of cervical remodeling and developing improved PTB diagnostics and therapeutics.