Feasibility of using ultrasonic shear waves to assess cervical remodelling during the gestation period

Prematurity affects 11% of the births and is the main cause of infant mortality. On the opposite case, labour has to be induced in approximately 23% of the pregnancies worldwide. However, it fails in 32% of the induced births, which is associated with fetal suffering. Both conditions are related with precocious and/or delayed cervical ripening. Quantitative and objective information about the temporal evolution of the cervical ripening may provide the development of a complementary method to identify cases at risk of preterm delivery and to assess the relevance of successful induction of labour, therefore allowing an efficient intervention. So far, however, no reliable clinical tool is available for quantitative and objective evaluation of cervical maturation. In current clinical practice, this biomechanical status is only subjectively assessed by digital palpation. In the past decade, different methods have been proposed to assess the pregnant cervix. Nevertheless, all of them were unsuccessful in objectively quantifying the histological, biochemical and mechanical changes that characterise the cervical remodelling during gestation. Among them, elastography has recently received particular attention in a quest for meaningful information on the degree of cervical stiffness/softness that may anticipate delivery much earlier than state-of-the-art geometry-based tests. Nevertheless, its potential application to assess the full complexity of cervical tissue still remains unclear. During gestation, in the so called cervical remodelling, several changes progressively occur in the structure of the cervical tissue. An increase in the hydration, disorganisation of collagen network and decrease in elasticity are observed. The collagen structure disorganisation is particularly complex: collagen fibres turn thicker and more wavy as the gestation progresses, while pores between collagen fibres become larger and separated. However, the link between stiffness and the cervical remodelling is not yet fully understood. In this thesis, the basic principles of solid mechanics are introduced to provide a connection between shear waves and cervical remodelling, facing towards the gestational assessment and its possible application to predict preterm birth and successful labour induction by shear wave elastography. In particular, we explore the feasibility of ultrasonic shear waves to assess the pregnant cervix. To this end, this thesis combines both experimental and numerical approaches. On the one hand, we evaluate the capability and reliability of shear wave elastography to assess cervical maturation in healthy pregnant women for first time. After showing its sensitivity to the cervix, a better insight into remodelling processes is the next proposed challenge achieved throughout this dissertation. For this purpose, we propose an animal model that allows to objectively define time control over the cervical maturation and provides physiologically relevant data that can then be connected to the elastographic measurements. The cervical ripening was induced by dexamethasone in some animals, while a group stood as control. Then, the artificially induced cervical maturation was monitored using shear waves elastography during 24 hours. Moreover, histological analyses and two-photon excitation microscopy, combining both Second Harmonic Generation and Two-photon Fluorescence microscopy contrasts, were used to investigate, at the microscopic scale, the architecture of cervical tissue. This study provides an insight about the cervical remodelling and the mechanical properties that are perceptible in elastography. On the other hand, a numerical approach has been developed to provide insight into the multi-scale problem and biochemical variables. The hypothesised link between shear waves and the hierarchical structure of cervical tissue, which is evidenced by the animal study, is analysed by a multi-scale computational model using the finite difference time domain technique to simulate shear wave propagation. As a third contribution, the key role of viscoelastic dissipation mechanisms in the interaction between shear waves and tissue micro-architecture is evidenced and studied in detail. First, a comparative study of the macro-scale viscoelastic moduli is developed, which manifests that a Maxwell model best describes shear waves-tissue interactions, contrarily to common belief in literature. In addition, computational models were used to analyse the influence of wave design parameters (i.e., excitation frequency) to optimally interrogate the relevant viscoelastic properties. The last contribution is a numerical histo-mechanical model used to link the variations of microscopic histological characteristics (both morphological and biochemical) with the macroscopic tissue-scale mechanical properties measurable by shear waves. We propose a multi-scale approach, which aims at describing the cervical remodelling, and combines three elements: collagen morphology, wave-tissue interactions and constitutive mixture theory. Parametric simulations were carried out for a broad range of mechanical and geometrical parameters that characterise the cervical extracellular matrix, showing that histological features can be quantitatively related to mechanical properties. Understanding the mechanisms that take place in normal pregnancy will allow a better comprehension of the cervical mechanical remodelling and lead to better methods of diagnosis of preterm birth and successful induction of labour.