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Birthing mechanics are poorly understood, though many injuries during childbirth are mechanical, like fetal and maternal tissue damage. Several biomechanical simulation models of parturition have been proposed to investigate birth, but many do not include the uterus. Additionally, most solid models rely on segmenting anatomical structures from clinical images to generate patient geometry, which can be time-consuming. This work presents two new parametric solid modeling methods for generating patient-specific, at-term uterine three-dimensional geometry. Building from an established method of modeling the sagittal uterine shape, this work improves the uterine coronal shape, especially where the fetal head joins the lower uterine wall. Solid models of the uterus and cervix were built from five at-term patients' magnetic resonance imaging (MRI) sets. Using anatomy measurements from MRI-segmented models, two parametric models were created--one that employs an averaged coronal uterine shape and one with multiple axial measurements of the coronal uterus. Through finite element analysis, the two new parametric methods were compared to the MRI-segmented high-fidelity method and a previously published elliptical low-fidelity method. A clear improvement in the at-term uterine shape was found using the two new parametric methods, and agreement in principal Lagrange strain directions was observed across all modeling methods. These methods provide an effective and efficient way to generate three-dimensional solid models of patient-specific maternal uterine anatomy, advancing possibilities for future research in computational birthing biomechanics. [ABSTRACT FROM AUTHOR]

[Display omitted] The mechanical function of the uterine cervix is critical for a healthy pregnancy. During pregnancy, the cervix undergoes significant softening to allow for a successful delivery. Abnormal cervical remodeling is suspected to contribute to preterm birth. Material constitutive models describing known biological shifts in pregnancy are essential to predict the mechanical integrity of the cervix. In this work, the material response of human cervical tissue under spherical indentation and uniaxial tensile tests loaded along different anatomical directions is experimentally measured. A deep-learning segmentation tool is applied to capture the tissue deformation during the uniaxial tensile tests. A 3-dimensional, equilibrium anisotropic continuous fiber constitutive model is formulated, considering collagen fiber directionality, fiber bundle dispersion, and the entropic nature of wavy cross-linked collagen molecules. Additionally, the universality of the material model is demonstrated by characterizing previously published mouse cervix mechanical data. Overall, the proposed material model captures the tension–compression asymmetric material responses and the remodeling characteristics of both human and mouse cervical tissue. The pregnant (PG) human cervix (mean locking stretch ζ = 2.4 , mean initial stiffness ξ = 12 kPa, mean bulk modulus κ = 0.26 kPa, mean dispersion b = 1.0) is more compliant compared with the nonpregnant (NP) cervix (mean ζ = 1.3 , mean ξ = 32 kPa, mean κ = 1.4 kPa, mean b = 1.4). Creating a validated material model, which describes the role of collagen fiber directionality, dispersion, and crosslinking, enables tissue-level biomechanical simulations to determine which material and anatomical factors drive the cervix to open prematurely. In this study, we report a 3D anisotropic hyperelastic constitutive model based on Langevin statistical mechanics and successfully describe the material behavior of both human and mouse cervical tissue using this model. This model bridges the connection between the extracellular matrix (ECM) microstructure remodeling and the macro mechanical properties change of the cervix during pregnancy via microstructure-associated material parameters. This is the first model, to our knowledge, to connect the the entropic nature of wavy cross-linked collagen molecules with the mechanical behavior of the cervix. Inspired by microstructure, this model provides a foundation to understand further the relationship between abnormal cervical ECM remodeling and preterm birth. Furthermore, with a relatively simple form, the proposed model can be applied to other fibrous tissues in the future. [ABSTRACT FROM AUTHOR]

Gelatin methacryloyl (GelMA) hydrogels are widely used for a variety of tissue engineering applications. The properties of gelatin can affect the mechanical properties of gelatin gels; however, the role of gelatin properties such as bloom strength on GelMA hydrogels has not yet been explored. Bloom strength is a food industry standard for describing the quality of gelatin, where higher bloom strength is associated with higher gelatin molecular weight. Here, we evaluate the role of bloom strength on GelMA hydrogel mechanical properties. We determined that both bloom strength of gelatin and weight percent of GelMA influenced both stiffness and viscoelastic ratio; however, only bloom strength affected diffusivity, permeability, and pore size. With this library of GelMA hydrogels of varying properties, we then encapsulated Swan71 trophoblast spheroids in these hydrogel variants to assess how bloom strength affects trophoblast spheroid morphology. Overall, we observed a decreasing trend of spheroid area and Feret diameter as bloom strength increased. In identifying clear relationships between bloom strength, hydrogel mechanical properties, and trophoblast spheroid morphology, we demonstrate that bloom strength should considered when designing tissue engineered constructs. [ABSTRACT FROM AUTHOR]

The uterus has critical biomechanical functions in pregnancy and undergoes dramatic material growth and remodeling from implantation to parturition. The intrinsic material properties of the human uterus and how they evolve in pregnancy are poorly understood. To address this knowledge gap and assess the heterogeneity of these tissues, the time-dependent material properties of all human uterine layers were measured with nanoindentation. The endometrium-decidua layer was found to be the least stiff, most viscous, and least permeable layer of the human uterus in nonpregnant and third-trimester pregnant tissues. In pregnancy, the endometrium-decidua becomes stiffer and less viscous with no material property changes observed in the myometrium or perimetrium. Additionally, uterine material properties did not significantly differ between third-trimester pregnant tissues with and without placenta accreta. The foundational data generated by this study will facilitate the development of physiologically accurate models of the human uterus to investigate gynecologic and obstetric disorders. [Display omitted] • Human uterine layers are distinct, heterogeneous and time-dependent. • Pregnancy alters the material properties of the maternal-fetal interface. • Largest dataset of uterine mechanical properties measured by nanoindentation. [ABSTRACT FROM AUTHOR]

The fetal membranes are an essential mechanical structure for pregnancy, protecting the developing fetus in an amniotic fluid environment and rupturing before birth. In cooperation with the cervix and the uterus, the fetal membranes support the mechanical loads of pregnancy. Structurally, the fetal membranes comprise two main layers: the amnion and the chorion. The mechanical characterization of each layer is crucial to understanding how each layer contributes to the structural performance of the whole membrane. The in-vivo mechanical loading of the fetal membranes and the amount of tissue stress generated in each layer throughout gestation remains poorly understood, as it is difficult to perform direct measurements on pregnant patients. Finite element analysis of pregnancy offers a computational method to explore how anatomical and tissue remodeling factors influence the load-sharing of the uterus, cervix, and fetal membranes. To aid in the formulation of such computational models of pregnancy, this work develops a fiber-based multilayer fetal membrane model that captures its response to previously published bulge inflation loading data. First, material models for the amnion, chorion, and maternal decidua are formulated, informed, and validated by published data. Then, the behavior of the fetal membrane as a layered structure was analyzed, focusing on the respective stress distribution and thickness variation in each layer. The layered computational model captures the overall behavior of the fetal membranes, with the amnion being the mechanically dominant layer. The inclusion of fibers in the amnion material model is an important factor in obtaining reliable fetal membrane behavior according to the experimental dataset. These results highlight the potential of this layered model to be integrated into larger biomechanical models of the gravid uterus and cervix to study the mechanical mechanisms of preterm birth. [Display omitted] • A fetal membrane model was developed using inflation data for the first time. • The multilayer model captured the behavior of each fetal membrane layer. • Including the amnion nonlinear behavior improved over existing fetal membrane models. • The amnion is the mechanically dominant layer of the fetal membrane. • The layered model can be integrated into larger models of the gravid uterus. [ABSTRACT FROM AUTHOR]

The cervix is a soft tissue exhibiting time-dependent behavior under mechanical loads. The cervix is a vital mechanical barrier to protect the growing fetus. The remodeling of the cervical tissue, characterized by an increase in time-dependent material properties, is necessary for a safe parturition. The failure of its mechanical function and accelerated tissue remodeling is hypothesized to lead to preterm birth, which is birth before 37 weeks of gestation. To understand the mechanism of the time-dependent behavior of the cervix under compressive states, we employ a porous-viscoelastic material model to describe a set of spherical indentation tests performed on nonpregnant and term pregnant tissue. A genetic algorithm-based inverse finite element analysis is used to fit the force-relaxation data by optimizing the material parameters, and the statistical analysis of the optimized material parameters is conducted on different sample groups. The force response is captured well using the porous-viscoelastic model. The indentation force-relaxation of the cervix is explained by the porous effects and the intrinsic viscoelastic properties of the extracellular matrix (ECM) microstructure. The hydraulic permeability obtained from the inverse finite element analysis agrees with the trend of the value directly measured previously by our group. The nonpregnant samples are found significantly more permeable than the pregnant samples. Within nonpregnant samples, the posterior internal os is found significantly less permeable than the anterior and posterior external os. The proposed model exhibits the superior capability to capture the force-relaxation response of the cervix under indentation, as compared to the conventional quasi-linear viscoelastic framework (range of r 2 of the porous-viscoelastic model 0.88–0.98 vs. quasi-linear model: 0.67–0.89). As a constitutive model with a relatively simple form, the porous-viscoelastic framework has the potential to be used to understand disease mechanisms of premature cervical remodeling, model contact of the cervix with biomedical devices, and interpret force readings from novel in-vivo measurement tools such as an aspiration device. [Display omitted] • A porous-viscoelastic model captures large compressive cervix material response. • A genetic-algorithm-based inverse FEA finds the best-fit material parameters. • Pregnant cervix is more permeable than nonpregnant, consistent with prior direct measurements. • The material model can be applied to fibrous soft tissues under large compressive deformation. [ABSTRACT FROM AUTHOR]

Preterm birth is the leading cause of neonatal mortality and morbidity worldwide. Spontaneous preterm birth is a complex, multifactorial condition in which cervical dysfunction plays an important role in some women. Current treatment options for cervical dysfunction include cerclage and supplemental progesterone. In addition, cervical pessary is being studied in research protocols. However, cerclage, supplemental progesterone and cervical pessary have well known limitations and there is a strong need for alternate treatment options. In this review, we discuss two novel interventions to treat cervical dysfunction: (1) injectable, silk protein-based biomaterials for cervical tissue augmentation (injectable cerclage) and (2) a patient-specific pessary. Three-dimensional computer simulation of the cervix is performed to provide a biomechanical rationale for the interventions. Further development of these novel interventions could lead to new treatment options for women with cervical dysfunction. [ABSTRACT FROM AUTHOR]

The mechanical integrity of the soft tissue structures supporting the fetus may play a role in maintaining a healthy pregnancy and triggering the onset of labor. Currently, the level of mechanical loading on the uterus, cervix, and fetal membranes during pregnancy is unknown, and it is hypothesized that the over-stretch of these tissues contributes to the premature onset of contractility, tissue remodeling, and membrane rupture, leading to preterm birth. The purpose of this review article is to introduce and discuss engineering analysis tools to evaluate and predict the mechanical loads on the uterus, cervix, and fetal membranes. Here we will explore the potential of using computational biomechanics and finite element analysis to study the causes of preterm birth and to develop a diagnostic tool that can predict gestational outcome. We will define engineering terms and identify the potential engineering variables that could be used to signal an abnormal pregnancy. We will discuss the translational ability of computational models for the better management of clinical patients. We will also discuss the process of model validation and the limitations of these models. We will explore how we can borrow from parallel engineering fields to push the boundary of patient care so that we can work toward eliminating preterm birth. [ABSTRACT FROM AUTHOR]

An appropriately timed cervical remodeling process is critical for a healthy delivery, yet little is known about the material property changes of the cervix in pregnancy because obtaining human tissue samples is difficult. Rodent models offer advantages including accurately timed pregnant tissues and genetically altered models. Determining the material properties of the mouse cervix, however, is challenging because of its small size and complex geometry. The aim of this study is to quantify cervical material property changes in a normal mouse pregnancy using a microstructurally-inspired porous fiber composite model. We mechanically test intact, whole, gestation-timed mouse cervix by pulling apart tensioned sutures through its inner canal. To interpret our mechanical testing results, we conduct an inverse finite element analysis, taking into account the combined loading state of the thick-walled cylindrical tissue. We fit the material model to previous osmotic swelling data and load-deformation data from this study using a nonlinear optimization scheme, and validate the model by predicting a separate set of deformation data. Overall, the proposed porous fiber composite model captures the mechanical behavior of the mouse cervix in large deformation. The evolution of cervical material parameters indicates that in a normal mouse pregnancy, the cervix begins to soften between day 6 and day 12 of a 19-day gestation period. The material parameter associated with the collagen fiber stiffness decreases from 3.4 MPa at gestation day 6 to 9.7e−4 MPa at gestation day 18, while the ground substance stiffness decreases from 2.6e−1 MPa to 7.0e−4 MPa. Statement of Significance Accelerated cervical remodeling can lead to extremely premature births. Little is known, however, about the material property changes of the cervix in pregnancy because pregnant human tissue samples are limited. Rodent models overcome this limitation and provide access to gestation-timed samples. Measuring the material property changes of the mouse cervix in pregnancy is challenging due to its small size and complex geometry. Here, we establish a combined experimental and modeling framework. We use this framework to determine the cervical material property changes throughout a normal mouse pregnancy. We present our experimental methods for mechanically testing whole, intact cervical tissue samples. We fit a porous fiber composite material model to the mechanical data and show that the mouse cervix begins to soften between day 6 and day 12 of a 19-day gestation period. [ABSTRACT FROM AUTHOR]

Abstract: The human cervix is an important mechanical barrier in pregnancy which must withstand the compressive and tensile forces generated from the growing fetus. Premature cervical shortening resulting from premature cervical remodeling and alterations of cervical material properties are known to increase a woman׳s risk of preterm birth (PTB). To understand the mechanical role of the cervix during pregnancy and to potentially develop indentation techniques for in vivo diagnostics to identify women who are at risk for premature cervical remodeling and thus preterm birth, we developed a spherical indentation technique to measure the time-dependent material properties of human cervical tissue taken from patients undergoing hysterectomy. In this study we present an inverse finite element analysis (IFEA) that optimizes material parameters of a viscoelastic material model to fit the stress–relaxation response of excised tissue slices to spherical indentation. Here we detail our IFEA methodology, report compressive viscoelastic material parameters for cervical tissue slices from nonpregnant (NP) and pregnant (PG) hysterectomy patients, and report slice-by-slice data for whole cervical tissue specimens. The material parameters reported here for human cervical tissue can be used to model the compressive time-dependent behavior of the tissue within a small strain regime of 25%. [Copyright &y& Elsevier]

Abstract: Growth and remodeling of biological tissues involves mass exchanges between soluble building blocks in the tissue's interstitial fluid and the various constituents of cells and the extracellular matrix. As the content of these various constituents evolves with growth, associated material properties, such as the elastic modulus of the extracellular matrix, may similarly evolve. Therefore, growth theories may be formulated by accounting for the evolution of tissue composition over time in response to various biological and mechanical triggers. This approach has been the foundation of classical bone remodeling theories that successfully describe Wolff's law by establishing a dependence between Young's modulus and bone apparent density and by formulating a constitutive relation between bone mass supply and the state of strain. The goal of this study is to demonstrate that adding tissue composition as state variables in the constitutive relations governing the stress–strain response and the mass supply represents a very general and straightforward method to model interstitial growth and remodeling in a wide variety of biological tissues. The foundation for this approach is rooted in the framework of mixture theory, which models the tissue as a mixture of multiple solid and fluid constituents. A further generalization is to allow each solid constituent in a constrained solid mixture to have its own reference (stress-free) configuration. Several illustrations are provided, ranging from bone remodeling to cartilage tissue engineering and cervical remodeling during pregnancy. [Copyright &y& Elsevier]

Abstract: An in vitro inflation test method was developed to characterize the mechanical behavior of the bovine posterior sclera. The method used digital image correlation to provide a spatially resolved, full-field deformation map of the surface of the posterior sclera in response to controlled pressurization. A series of experiments were performed in the range of 2–6kPa (15–45mmHg) to characterize the load–unload displacement response at various pressure rates and the time-dependent displacement response at different applied pressures. The magnitude of the displacement was largest in the peripapillary region, mainly between the apex and the optic nerve head. Further, the results showed that bovine scleral tissue exhibited nonlinear and viscoelastic behavior characterized by a rate-dependent displacement response, hysteresis during unloading and creep. The creep rate was insensitive to the applied pressure, suggesting that the tissue can be modeled as a quasilinear viscoelastic material in the physiological pressure range of 2–6kPa. [ABSTRACT FROM AUTHOR]

Background: Premature cervical remodeling resulting in spontaneous preterm birth may begin with premature failure or relaxation at the internal os (termed "funneling"). To date, we do not understand why the internal os fails or why funneling occurs in some cases of premature cervical remodeling. Although the human cervix is thought to be mostly collagen with minimal cellular content, cervical smooth muscle cells are present in the cervix and can cause cervical tissue contractility.Objective: To understand why the internal os relaxes or why funneling occurs in some cases of premature cervical remodeling, we sought to evaluate cervical smooth muscle cell content and distribution throughout human cervix and correlate if cervical smooth muscle organization influences regional cervical tissue contractility.Study Design: Using institutional review board-approved protocols, nonpregnant women <50 years old undergoing hysterectomy for benign indications were consented. Cervical tissue from the internal and external os were immunostained for smooth muscle cell markers (α-smooth muscle actin, smooth muscle protein 22 calponin) and contraction-associated proteins (connexin 43, cyclooxygenase-2, oxytocin receptor). To evaluate cervical smooth muscle cell morphology throughout the entire cervix, whole cervical slices were obtained from the internal os, midcervix, and external os and immunostained with smooth muscle actin. To correlate tissue structure with function, whole slices from the internal and external os were stimulated to contract with 1 μmol/L of oxytocin in organ baths. In separate samples, we tested if the cervix responds to a common tocolytic, nifedipine. Cervical slices from the internal os were treated with oxytocin alone or oxytocin + increasing doses of nifedipine to generate a dose response and half maximal inhibitory concentration. Student t test was used where appropriate.Results: Cervical tissue was collected from 41 women. Immunohistochemistry showed cervical smooth muscle cells at the internal and external os expressed mature smooth muscle cell markers and contraction-associated proteins. The cervix exhibited a gradient of cervical smooth muscle cells. The area of the internal os contained 50-60% cervical smooth muscle cells that were circumferentially organized in the periphery of the stroma, which may resemble a sphincter-like pattern. The external os contained approximately 10% cervical smooth muscle cells that were randomly scattered in the tissue. In organ bath studies, oxytocin stimulated the internal os to contract with more than double the force of the external os (1341 ± 693 vs 523 ± 536 integrated grams × seconds, respectively, P = .009). Nifedipine significantly decreased cervical tissue muscle force compared to timed vehicle control (oxytocin alone) at doses of 10(-5) mol/L (vehicle 47% ± 15% vs oxytocin + nifedipine 24% ± 16%, P = .007), 10(-4) mol/L (vehicle 46% ± 16% vs oxytocin + nifedipine -4% ± 20%, P = .003), and 10(-3) mol/L (vehicle 42% ± 14% vs oxytocin + nifedipine -15% ± 18%, P = .0006). The half maximal inhibitory concentration for nifedipine was 1.35 × 10(-5) mol/L.Conclusion: Our findings suggest a new paradigm for cervical tissue morphology-one that includes the possibility of a specialized sphincter at the internal os. This new paradigm introduces novel avenues to further investigate potential mechanisms of normal and premature cervical remodeling. [ABSTRACT FROM AUTHOR]

Objective The mechanical strength of the cervix relies on the cross-linking of the tissue’s collagen network. Clinically, the internal os is functionally distinct from the external os. We sought to detect specific collagen cross-links in human cervical tissue and determine whether cross-link profiles were similar at the internal and external os. Study Design Transverse slices of cervical tissue were obtained at the internal and external os from 13 nonpregnant, premenopausal women undergoing a benign hysterectomy. To understand how cross-links were distributed throughout the entire cervix and at the internal and external os, biopsies were obtained from 3 circumferential zones in 4 quadrants from each slice. Biopsies were pulverized, lyophilized, reduced with sodium borohydride, hydrolyzed with hydrochloric acid, and reconstituted in heptafluorobutyric acid buffer. Hydroxyproline was measured by ultraperformance liquid chromatography-electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS), converted to total collagen, and normalized by dry weight. Collagen cross-links pyridinoline (PYD), deoxypyridinoline (DPD), dihydroxylysinonorleucine (DHLNL), and the nonenzymatic advanced glycation end product pentosidine (PEN) were measured by UPLC-ESI-MS/MS and reported as cross-link density ratio (cross-link/total collagen). Generalized estimated equation analysis was used to compare results between the internal and external os and to compare quadrants and zones within slices from the internal and external os to determine if cross-link profiles were similar. Results A total of 592 samples from 13 patients were analyzed. Collagen cross-links are detectable in the human cervix by UPLC-ESI-MS/MS. When comparing all samples from the internal and external os, similar levels of collagen content, PYD, DHLNL, and DPD were found, but PEN density was higher at the external os (0.005 vs 0.004, P = .001). When comparing all internal os samples, significant heterogeneity was found in collagen content and cross-link densities across zones and quadrants. The external os exhibited heterogeneity only across zones. Conclusion Collagen cross-links (PYD, DPD, DHLNL, and PEN) are detectable by UPLC-ESI-MS/MS in the human cervix. The internal os exhibits significant collagen cross-link heterogeneity compared with the external os. Further studies are needed to evaluate how collagen cross-link heterogeneity correlates to the mechanical strength and function of the human cervix. [ABSTRACT FROM AUTHOR]