Biomechanical pregnant pelvic system model and numerical simulation of childbirth: impact of delivery on the uterosacral ligaments, preliminary results.

INTRODUCTION AND HYPOTHESIS: We created a pregnant woman pelvic model to perform a simulation of delivery to understand the pathophysiology of urogenital prolapse by studying the constraints on the pelvic components (muscles, ligaments, pelvic organs) during childbirth. These simulations will also provide valuable tools to understand and teach obstetrical mechanics. METHODS: We built a numerical model of the pelvic system from a term pregnant woman, using the finite element method on a mesh built from magnetic resonance images of a nulliparous pregnant woman. Mechanical properties of pelvic tissues already determined by the team were adapted to account for pregnancy. RESULTS: The system allows delivery to be simulated. When a fetal head at the 50th percentile for the term goes through the pelvic system, uterosacral ligaments undergo a deformation of around 30 %. Uterosacral ligaments are the major pelvic sustaining structures, their lesion may be a potential cause of urogenital prolapse. We built a model of childbirth as a function of pregnancy term by varying volumes of fetal head and uterus. The impact on uterosacral ligaments is higher when the fetal head is larger. CONCLUSIONS: Our modelling is rather complete considering that it involves many organs including ligaments. It allows us to analyse the effect of childbirth on uterosacral ligaments and to understand how they impact on pelvic statics. First results are promising, but optimisation and future simulations will be needed. We also plan to simulate various delivery scenarios (cephalic, breech presentation, instrumental extraction), which will be useful to study perineal lesions and also to teach obstetrical mechanics.

The swelling behavior of the mouse cervix: Changing kinetics with osmolarity and the role of hyaluronan in pregnancy.

The cervical remodeling process during pregnancy is characterized by progressive compositional and structural changes in the tissues extra-cellular matrix (ECM). Appropriately timed remodeling is critical for healthy gestation and prevention of premature cervical softening leading to preterm birth (PTB). Modification of the ECM glycosaminoglycans (GAGs) content with advancing pregnancy, especially the non-sulfated GAG hyaluronan (HA), is a fundamental change associated with cervical remodeling. While GAGs have numerous physiological roles, the mechanical consequence of evolving GAG content on cervical structure-function behavior remains an open question. Additionally, an understanding of cervical swelling properties, postulated to be regulated in part by GAGs, is required for the appropriate definition of a reference configuration for mechanical tests and to enhance biological understanding. To investigate cervical swelling, osmotic loading tests are conducted on isolated wild type mouse cervices throughout pregnancy. These tests are performed in various osmolarity solutions to assess the influence of the media on swelling kinetics. A genetically altered strain of mice with depletion of cervical HA is also tested to elucidate the contribution of HA to tissue swelling. Results show ex vivo cervical swelling is significant with volume changes ranging from 20 to 100% after 3h of free swelling. The swelling kinetics depend highly on osmolarity of the media and is altered with advancing pregnancy. The contribution of HA to swelling is only significant in hypo-osmotic solution when HA cervical content is high at the end of pregnancy. In summary, it is critical to account for swelling deformation mechanisms after excision in mechanical experiments. STATEMENT OF SIGNIFICANCE: The cervical extracellular matrix (ECM) undergoes drastic changes to fulfill the functional change of the cervix during pregnancy. Inappropriate timing for this transformation can result in preterm birth, a severe clinical challenge. One of the fundamental changes of the cervical ECM is the significant modification of the glycosaminoglycan content, especially hyaluronan (HA), which is thought to contribute significantly to the swelling and mechanical properties of the cervix. This study aims to measure the swelling kinetics of cervical tissue during pregnancy and to investigate the role of HA in these swelling tendencies. Results show the significant swelling of cervical tissue, which evolves as pregnancy progresses, highlighting a key material property feature of the remodeled cervix. Using a mouse strain with a cervical HA depletion, this work shows HA contributes to the swelling trends of late-term cervical tissue, in a hypo-osmotic solution.

The mechanical response of the mouse cervix to tensile cyclic loading in term and preterm pregnancy.

A well-timed modification of both the collagen and elastic fiber network in the cervix during pregnancy accompanies the evolution of tissue mechanical parameters that are key to a successful pregnancy. Understanding of the cervical mechanical behaviour along normal and abnormal pregnancy is crucial to define the molecular events that regulate remodeling in term and preterm birth (PTB). In this study, we measured the mechanical response of mouse cervical tissue to a history of cyclic loading and quantified the tissue's ability to recover from small and large deformations. Assessments were made in nonpregnant, pregnant (gestation days 6, 12, 15 and 18) and mouse models of infection mediated PTB treated with lipopolysaccharide on gestation d15 (LPS treated) and hormone withdrawal mediated PTB on gestation d15 (RU486 treated). The current study uncovers the contributions of collagen and elastic fiber networks to the progressive change in mechanical function of the cervix through pregnancy. Premature cervical remodeling induced on gestation day 15 in the LPS infection model is characterized by distinct mechanical properties that are similar but not identical to mechanical properties at term ripening on day 18. Remodeling in the LPS infection model results in a weaker cervix, unable to withstand high loads. In contrast, the RU486 preterm model resembles the cyclic mechanical behaviour seen for term d18 cervix, where the extremely compliant tissue is able to withstand multiple cycles under large deformations without breaking. The distinct material responses to load-unload cycles in the two PTB models matches the differing microstructural changes in collagen and elastic fibers in these two models of preterm birth. Improved understanding of the impact of microstructural changes to mechanical performance of the cervix will provide insights to aid in the development of therapies for prevention of preterm birth. STATEMENT OF SIGNIFICANCE: Preterm Birth (PTB) still represents a serious challenge to be overcome, considering its implications on infant mortality and lifelong health consequences. While the causes and etiologies of PTB are diverse and yet to be fully elucidated, a common pathway leading to a preterm delivery is premature cervical remodeling. Throughout pregnancy, the cervix remodels through changes of its microstructure, thus altering its mechanical properties. An appropriate timing for these transformations is critical for a healthy pregnancy and avoidance of PTB. Hence, this study aims at understanding how the mechanical function of the cervix evolves during a normal and preterm pregnancy. By performing cyclic mechanical testing on cervix samples from animal models, we assess the cervix's ability to recover from moderate and severe loading. The developed methodology links mechanical parameters to specific microstructural components. This work identifies a distinct biomechanical signature associated with inflammation mediated PTB that differs from PTB induced by hormone withdrawal and from normal term remodeling.

Geometry of an inflated membrane in elliptic bulge tests: Evaluation of an ellipsoidal shape approximation by stereoscopic digital image correlation measurements.

Elliptic bulge tests are conducted on liver capsule, a fibrous connective membrane, associated with a field measurement method to assess the global geometry of the samples during the tests. The experimental set up is derived from a previous experimental campaign of bulge tests under microscope. Here, a stereoscopic Digital Image Correlation (DIC) system is used to measure global parameters on the test and investigate some assumptions made on the testing conditions which could not been assessed with microscopic measurements. In particular, the assumption of an ellipsoidal shape of the inflated membrane is tested by comparing the actual sample shape measured by stereoscopic DIC with an idealized ellipsoidal shape. Results indicate that a rather constant gap exists between the idealized and actual position. The approximation in the calculation of a macroscopic strain through analytical modeling of the test is estimated here. The study of the liver capsule case shows that important differences can be observed in strain calculation depending on the method and assumptions taken. Therefore, analytical modeling of mechanical tests through ellipsoidal approximation needs to be carefully evaluated in every application. Here the field measurement allows assessing the validity of these modeling assumptions. Moreover, it gives precious details about the boundary conditions of the bulge test and revealed the heterogeneous clamping, highlighted by strain concentrations.

Affine kinematics in planar fibrous connective tissues: an experimental investigation.

The affine transformation hypothesis is usually adopted in order to link the tissue scale with the fibers scale in structural constitutive models of fibrous tissues. Thanks to the recent advances in imaging techniques, such as multiphoton microscopy, the microstructural behavior and kinematics of fibrous tissues can now be monitored at different stretching within the same sample. Therefore, the validity of the affine hypothesis can be investigated. In this paper, the fiber reorientation predicted by the affine assumption is compared to experimental data obtained during mechanical tests on skin and liver capsule coupled with microstructural imaging using multiphoton microscopy. The values of local strains and the collagen fibers orientation measured at increasing loading levels are used to compute a theoretical estimation of the affine reorientation of collagen fibers. The experimentally measured reorientation of collagen fibers during loading could not be successfully reproduced with this simple affine model. It suggests that other phenomena occur in the stretching process of planar fibrous connective tissues, which should be included in structural constitutive modeling approaches.

Characterizing liver capsule microstructure via in situ bulge test coupled with multiphoton imaging.

The characterization of biological tissue at the microscopic scale is the starting point of many applications in tissue engineering and especially in the development of structurally based constitutive models. In the present study, focus is made on the liver capsule, the membrane encompassing hepatic parenchyma, which takes a huge part in liver mechanical properties. An in situ bulge test experiment under a multiphoton microscope has been developed to assess the microstructure changes that arise with biaxial loading. Multiphoton microscopy allows to observe the elastin and collagen fiber networks simultaneously. Thus a description of the microstructure organization of the capsule is given, characterizing the shapes, geometry and arrangement of fibers. The orientation of fibers is calculated and orientation distribution evolution with loading is given, in the case of an equibiaxial and two non equibiaxial loadings, thanks to a circular and elliptic set up of the bulge test. The local strain fields have also been computed, by the mean of a photobleaching grid, to get an idea of what the liver capsule might experience when subjected to internal pressure. Results show that strain fields present some heterogeneity due to anisotropy. Reorientation occurs in non equibiaxial loadings and involves fibers layers from the inner to the outer surface as expected. Although there is a fiber network rearrangement to accommodate with loading in the case of equibiaxial loading, there is no significant reorientation of the main fibers direction of the different layers.

Photobleaching as a tool to measure the local strain field in fibrous membranes of connective tissues.

Connective tissues are complex structures which contain collagen and elastin fibers. These fiber-based structures have a great influence on material mechanical properties and need to be studied at the microscopic scale. Several microscopy techniques have been developed in order to image such microstructures; among them are two-photon excited fluorescence microscopy and second harmonic generation. These observations have been coupled with mechanical characterization to link microstructural kinematics to macroscopic material parameter evolution. In this study, we present a new approach to measure local strain in soft biological tissues using a side-effect of fluorescence microscopy: photobleaching. Controlling the loss of fluorescence induced by photobleaching, we create a pattern on our sample that we can monitor during mechanical loading. The image analysis allows three-dimensional displacements of the patterns at various loading levels to be computed. Then, local strain distribution is derived using the finite element discretization on a four-node element mesh created from our photobleached pattern. Photobleaching tests on a human liver capsule have revealed that this technique is non-destructive and does not have any impact on mechanical properties. This method is likely to have other applications in biological material studies, considering that all collagen-elastin fiber-based biological tissues possess autofluorescence properties and thus can be photobleached.