Competing mechanisms of stress-assisted diffusivity and stretch-activated currents in cardiac electromechanics

We numerically investigate the role of mechanical stress in modifying the conductivity properties of the cardiac tissue and its impact in computational models for cardiac electromechanics. We follow a theoretical framework recently proposed in [Cherubini, Filippi, Gizzi, Ruiz-Baier, JTB 2017], in the context of general reaction-diffusion-mechanics systems using multiphysics continuum mechanics and finite elasticity. In the present study, the adapted models are compared against preliminary experimental data of pig right ventricle fluorescence optical mapping. These data contribute to the characterization of the observed inhomogeneity and anisotropy properties that result from mechanical deformation. Our novel approach simultaneously incorporates two mechanisms for mechano-electric feedback (MEF): stretch-activated currents (SAC) and stress-assisted diffusion (SAD); and we also identify their influence into the nonlinear spatiotemporal dynamics. It is found that i) only specific combinations of the two MEF effects allow proper conduction velocity measurement; ii) expected heterogeneities and anisotropies are obtained via the novel stress-assisted diffusion mechanisms; iii) spiral wave meandering and drifting is highly mediated by the applied mechanical loading. We provide an analysis of the intrinsic structure of the nonlinear coupling using computational tests, conducted using a finite element method. In particular, we compare static and dynamic deformation regimes in the onset of cardiac arrhythmias and address other potential biomedical applications

To Be, or Not to Be: Cellular Homeostasis to Mechanical Perturbations

Mechanical homeostasis is an emerging mechanobiology concept that describes the critical biological process to maintain whole-cell/tissue physiology against forces and deformation arising both intra- and extracellularly. Dysregulation of mechanical homeostasis has important implications in pathophysiological conditions such as developmental defect, cardiovascular and pulmonary diseases, and cancer. Mechanical homeostasis has been commonly investigated at molecular, cellular, tissue levels and beyond. However, in mechanical homeostasis collective dynamics at smaller scales and its functional relationship with emergent system-level properties at larger scales remains elusive. The major contribution of this dissertation is to provide a detailed picture of the functional link between molecular and subcellular events and apparent cellular behaviors under mechanical perturbations. A novel suite of technologies, involving microfabrication, live-cell imaging, high-throughput and multidimensional image processing, and mechanical characterization, have been developed and implemented in this research for the live-cell study of both subcellular and cellular aspects of mechanical homeostasis. By utilizing these techniques, we performed cell stretch experiments and quantitative measurements of biomechanical and biochemical responses with a spatiotemporal resolution to examine cell behaviors upon mechanical perturbation. Our data have revealed that cellular mechanical homeostasis is an emergent phenomenon driven by collective and graduated, yet non-homeostatic, subcellular behaviors (“subcellular rheostasis”) that follow distinct mechanosensitive compensatory paths. We have for the first time shown that subcellular dynamics would observe patterns different from that at the single-cell level. Further investigations have revealed that impairment to the extracellular matrix (ECM) – focal adhesion (FA) – cytoskeleton (CSK) mechanical linkage can lead to an effective exit from cellular mechanical homeostasis by skewing the subcellular rheostasis pattern of FAs, which might be a sensitive gating mechanism of cellular homeostasis. Lastly, a mechano-biophysical model has been constructed in this work to quantitatively recapitulate experimental observations of subcellular rheostasis and its perturbation by different drug treatments. Cross-examination of experimental and theoretical modeling results has unveiled the regulatory roles of different mechanosensitive machineries including catch-slip bonds and myosin motor activity in governing the emergence of cellular mechanical homeostasis.PHDMechanical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/135780/1/shinuow_1.pd

Forward Electrophysiological Modeling and Inverse Problem for Uterine Contractions during Pregnancy

Uterine contractile dysfunction during pregnancy is a significant healthcare challenge that imposes heavy medical and financial burdens on both human beings and society. In the U.S., about 12% of babies are born prematurely each year, which is a leading cause of neonatal mortality and increases the possibility of having subsequent health problems. Post-term birth, in which a baby is born after 42 weeks of gestation, can cause risks for both the newborn and the mother. Currently, there is a limited understanding of how the uterus transitions from quiescence to excitation, which hampers our ability to detect labor and treat major obstetric syndromes associated with contractile dysfunction. Therefore, it is critical to develop objective methods to investigate the underlying contractile mechanism using a non-invasive sensing technique. This dissertation focuses on the multiscale forward electromagnetic modeling of uterine contractile activities and the inverse estimation of underlying source currents from abdominal magnetic field measurements. We develop a realistic multiscale forward electromagnetic model of uterine contractions in the pregnant uterus, taking into account current electrophysiological and anatomical knowledge of the uterus. Previous models focused on generating contractile forces at the organ level or on ionic concentration changes at the cellular level. Our approach is to characterize the electromagnetic fields of uterine contractions jointly at the cellular, tissue, and organ levels. At the cellular level, focusing on both plateau-type and bursting-type action potentials, we introduce a generalized version of the FitzHugh-Nagumo equations and analyze its response behavior based on bifurcation theory. To represent the anisotropy of the myometrium, we introduce a random conductivity tensor model for the fiber orientations at the tissue level. Specifically, we divide the uterus into contiguous regions, each of which is assigned a random fiber angle. We also derive analytical expressions for the spiking frequency and propagation velocity of the bursting potential. At the organ level, we propose a realistic four-compartment volume conductor, in which the uterus is modeled based on the magnetic resonance imaging scans of a near-term woman and the abdomen is curved to match the device used to take the magnetomyography measurements. To mimic the effect of the sensing direction, we incorporate a sensor array model on the surface of abdomen. We illustrate our approach using numerical examples and compute the magnetic field using the finite element method. Our results show that fiber orientation and initiation location are the key factors affecting the magnetic field pattern, and that our multiscale forward model flexibly characterizes the limited-propagation local contractions at term. These results are potentially important as a tool for interpreting the non-invasive measurements of uterine contractions. We also consider the inverse problem of uterine contractions during pregnancy. Our aim is to estimate the myometrial source currents that generate the external magnetomyography measurements. Existing works approach this problem using synthetic electromyography data. Our approach instead proceeds in two stages: develop a linear approximation model and conduct the estimation. In the first stage, we derive a linear approximation model of the sensor-oriented magnetic field measurements with respect to source current dipoles in the myometrium, based on a lead-field matrix. In particular, this lead-field matrix is analytically computed from distributed current dipoles in the myometrium according to quasi-static Maxwell\u27s equations, using the finite element method. In the second stage, we solve a constrained least-squares problem to estimate the source currents, from which we predict the intrauterine pressure. We demonstrate our approach through numerical examples with synthetic data that are generated using our multiscale forward model. In the simulations, we assume that the excitation is located at the fundus of the uterus. We also illustrate our approach using real data sets, one of which has simultaneous contractile pressure measurements. The results show that our method well captures the short-distance propagation of uterine contractile activities during pregnancy, the change of excitation area in subsequent contractions or even in a single contraction, and the timing of uterine contractions. These findings are helpful in understanding the physiological and functional properties of the uterus, potentially enabling the diagnosis of labor and the treatment of obstetric syndromes associated with contractile dysfunction such as preterm birth and post-term birth

Coordination Mechanisms of Mammalian Embryo Implantation

A direct interaction between the extraembryonic and the uterine tissues during embryo implantation generates a unique biomechanical context for the blastocyst. However, our mechanistic understanding of the regulation of blastocyst morphogenesis during implantation is limited by the inaccessibility in vivo and remaining challenges to model feto-maternal interaction ex vivo. To overcome these limitations, I applied microfabrication and biomaterial engineering to model biomechanical cues of the murine intrauterine environment ex vivo with high precision and tunability. I identify that embryo-uterine adhesion and tissue geometry are critical for successful peri-implantation development. In a specific parameter range, closely resembling in utero conditions, the 3D geometrically patterned hydrogel supports mouse blastocysts through implantation and enables robust peri-implantation morphogenesis; promotes the development of the Reichert’s membrane and all extraembryonic tissues, including giant trophoblast, which directly interacts with the uterus. To monitor in toto peri-implantation embryo dynamics, the culture method was integrated with inverted view InVi-SPIM and multiview MuVi-SPIM light-sheet microscopes. I show that integrin-mediated adhesion by the mural trophectoderm provides the mechanism of trophectoderm tension release, driving the morphogenesis of the extraembryonic ectoderm and egg cylinder patterning. Moreover, the embryo-uterine adhesion enables collective trophoblast migration, dependent on Rac1. Finally, I demonstrate that the uterine tissue geometry spatially coordinates collective trophoblast migration to delineate space for egg cylinder growth. Together, this study reveals essential mechanisms of dynamic embryo-uterus interactions during peri-implantation development

Competing Mechanisms of Stress-Assisted Diffusivity and Stretch-Activated Currents in Cardiac Electromechanics

We numerically investigate the role of mechanical stress in modifying the conductivity properties of cardiac tissue, and also assess the impact of these effects in the solutions generated by computational models for cardiac electromechanics. We follow the recent theoretical framework from Cherubini et al. (2017), proposed in the context of general reaction-diffusion-mechanics systems emerging from multiphysics continuum mechanics and finite elasticity. In the present study, the adapted models are compared against preliminary experimental data of pig right ventricle fluorescence optical mapping. These data contribute to the characterization of the observed inhomogeneity and anisotropy properties that result from mechanical deformation. Our novel approach simultaneously incorporates two mechanisms for mechano-electric feedback (MEF): stretch-activated currents (SAC) and stress-assisted diffusion (SAD); and we also identify their influence into the nonlinear spatiotemporal dynamics. It is found that (i) only specific combinations of the two MEF effects allow proper conduction velocity measurement; (ii) expected heterogeneities and anisotropies are obtained via the novel stress-assisted diffusion mechanisms; (iii) spiral wave meandering and drifting is highly mediated by the applied mechanical loading. We provide an analysis of the intrinsic structure of the nonlinear coupling mechanisms using computational tests conducted with finite element methods. In particular, we compare static and dynamic deformation regimes in the onset of cardiac arrhythmias and address other potential biomedical applications