## Section: New Results

### Mathematical and Mechanical Modeling

#### Microscopic model of collagen fiber

Participants : Florent Wijanto, Matthieu Caruel, Jean-Marc Allain [correspondant] .

Our studies on collagen tissues have shown that the collagen fibers are able to elongate inelastically under stretch. In tendon, this effect has been attributed to the non-permanent cross-bridges which connect the different collagen fibrils (to assemble a fiber). This sliding effect appears experimentally to be reversible (at least partially) if the tissue is left long enough at its initial resting length. However, this sliding is classically included as an irreversible plastic response, or as a damage of the tissue. We are building a model based on a stochastic description of the binding and unbinding of the cross-bridges. This approach will enable us to have a microscopically based picture of the sliding, which will be able to explain some alteration in case of ageing or of pathological alterations of the tissue. At the moment, we have shown the importance of the density of cross-bridges in the cooperative response of the system. A publication is in preparation on the topic.

#### Stochastic modeling of chemical-mechanical coupling in striated muscles

Participants : Matthieu Caruel, Dominique Chapelle [correspondant] , Philippe Moireau.

We propose a chemical-mechanical model of myosin heads in sarcomeres, within the classical description of rigid sliding filaments. In our case, myosin heads have two mechanical degrees-of-freedom (dofs) – one of which associated with the so-called power stroke – and two possible chemical states, i.e. bound to an actin site or not. Our major motivations are twofold: (1) to derive a multiscale coupled chemical-mechanical model, and (2) to thus account – at the macroscopic scale – for mechanical phenomena that are out of reach for classical muscle models. This model is first written in the form of Langevin stochastic equations, and we are then able to obtain the corresponding Fokker-Planck partial differential equations governing the probability density functions associated with the mechanical dofs and chemical states. This second form is important, as it allows to monitor muscle energetics, and also to compare our model with classical ones, such as the Huxley’57 model to which our equations are shown to reduce under two different types of simplifying assumptions. This provides insight, and gives a Langevin form for Huxley’57. We then show how we can calibrate our model based on experimental data – taken here for skeletal muscles – and numerical simulations demonstrate the adequacy of the model to represent complex physiological phenomena, in particular the fast isometric transients in which the power stroke is known to have a crucial role, thus circumventing a limitation of many classical models. This work is accepted for publication in BMMB.

#### The importance of the pericardium for cardiac biomechanics

Participant : Radomir Chabiniok [correspondant] .

The human heart is enclosed in the pericardial cavity. The pericardium consists of a layered thin sac and is separated from the myocardium by a thin film of fluid. It provides a fixture in space and frictionless sliding of the myocardium. The influence of the pericardium is essential for predictive mechanical simulations of the heart. However, there is no consensus on physiologically correct and computationally tractable pericardial boundary conditions. Here we propose to model the pericardial influence as a parallel spring and dashpot acting in normal direction to the epicardium. Using a four-chamber geometry, we compare a model with pericardial boundary conditions to a model with fixated apex. The influence of pericardial stiffness is demonstrated in a parametric study. Comparing simulation results to measurements from cine magnetic resonance imaging reveals that adding pericardial boundary conditions yields a better approximation with respect to atrioventricular plane displacement, atrial filling, and overall spatial approximation error. We demonstrate that this simple model of pericardial-myocardial interaction can correctly predict the pumping mechanisms of the heart as previously assessed in clinical studies. Utilizing a pericardial model can not only provide much more realistic cardiac mechanics simulations but also allows new insights into pericardial-myocardial interaction which cannot be assessed in clinical measurements yet. The work was accepted for publication in Biomechanics and Modeling in Mechanobiology [26], and is a joint work with Technical University in Munich, Germany (group of W.A. Wall) and Bernoulli Institute for Mathematics at University of Groningen, The Netherlands (C. Bertoglio).

#### Solving 2D linear isotropic elastodynamics by means of scalar potentials: a new challenge for finite elements

Participants : Sébastien Imperiale, Patrick Joly [Poems] .

In this work we present a method for the computation of numerical solutions of 2D homogeneous isotropic elastodynamics equations by solving scalar wave equations. These equations act on the potentials of a Helmholtz decomposition of the displacement field and are decoupled inside the propagation domain. We detail how these equations are coupled at the boundary depending on the nature of the boundary condition satisfied by the displacement field. After presenting the case of rigid boundary conditions, that presents no specific difficulty, we tackle the challenging case of free surface boundary conditions that presents severe stability issues if a straightforward approach is used. We introduce an adequate functional framework as well as a time domain mixed formulation to circumvent these issues. Numerical results confirm the stability of the proposed approach.

#### Lung multiscale poromechanical modeling, from breathing to pulmonary fibrosis-induced chronic remodeling

Participants : Cécile Patte [correspondant] , Martin Genet, Dominique Chapelle.

Pulmonary diseases are about to become the third cause of death in the world. One on them, Idiopathic Pulmonary Fibrosis (IPF), which involves thickening, stiffening and destruction the alveolar walls, remains poorly understood, diagnosed and treated. It has been hypothesized, however, that IPF involves a mechanical vicious circle, where fibrosis induces higher stresses, which in turns favors fibrosis. In this project, we intend to better understand the role of mechanics in the disease progression, in order to improve diagnosis and prognosis. We model the lung behavior during breathing at organ-scale, based on a poromechanical theory, previously established in the team. Then we estimate the regional mechanical properties of the lung, based on clinical data. In the future, the procedure can be used as a prognostic tool by the clinicians.

#### Mathematical modelling of transient shear wave elastography in the heart

Participants : Federica Caforio [correspondant] , Sébastien Imperiale.

The aim of this work is to provide a mathematical model of the excitation and the resulting shear wave propagation in Acoustic Radiation Force (ARF)-based shear wave cardiac elastography. Our approach is based on asymptotic analysis; more precisely, it consists in considering a family of problems, parametrised by a small parameter inversely proportional to the excitation frequency of the probes, the viscosity and the velocity of pressure wave propagation. We derive a simplified model for the expression of the ARF by investigating the limit behaviour of the solution when the small parameter goes to zero. By formal asymptotic analysis - an asymptotic expansion of the solution is used - we show that the leading order term of the expansion is the underlying nonlinear cardiac mechanics. Subsequently, two corrector terms are computed. The first is a fast-oscillating pressure wave generated by the probes, solution of a Helmholtz equation at every time instant. The second corrector term consists in an elastic field with prescribed divergence, having a function of the first corrector as a source term. This field corresponds to the shear acoustic wave induced by the ARF. We also confirm that, in cardiac mechanics, the presence of viscosity in the model is essential to derive an expression of the shear wave propagation from the ARF, and that this phenomenon is related to the nonlinearity of the partial differential equation.

#### Analysis and calibration of a linear model for structured cell populations with unidirectional motion : Application to the morphogenesis of ovarian follicles

Participants : Frédérique Clément, Frédérique Robin [correspondant] , Romain Yvinec [INRA] .

In [41], we have analyzed a multi-type age dependent model for cell populations subject to unidirectional motion, in both a stochastic and deterministic framework. Cells are distributed into successive layers; they may divide and move irreversibly from one layer to the next. We have adapted results on the large-time convergence of PDE systems and branching processes to our context, where the Perron-Frobenius or Krein-Rutman theorems cannot be applied. We have derived explicit analytical formulas for the asymptotic cell number moments, and the stable age distribution. We have illustrated these results numerically and we have applied them to the study of the morphodynamics of ovarian follicles. We have proven the structural parameter identifiability of our model in the case of age independent division rates. Using a set of experimental biological data, we have estimated the model parameters to fit the changes in the cell numbers in each layer during the early stages of follicle development.

#### A multiscale mathematical model of cell dynamics during neurogenesis in the mouse cerebral cortex

Participants : Frédérique Clément [correspondant] , Marie Postel [Sorbonne Universités] .

Work in collaboration with Sylvie Schneider-Maunoury (Sorbonne Universités), Alice Karam (Sorbonne Universités), Guillaume Pézeron (MNHN). Neurogenesis in the murine cerebral cortex involves the coordinated divisions of two main types of progenitor cells, whose numbers, division modes and cell cycle durations set up the final neuronal output. To understand the respective roles of these factors in the neurogenesis process, we have combined experimental in vivo studies with mathematical modeling and numerical simulations of the dynamics of neural progenitor cells [43]. A special focus has been put on the population of intermediate progenitors (IPs), a transit amplifying progenitor type critically involved in the size of the final neuron pool. Our multiscale formalism describing IP dynamics allows one to track the progression of cells along the subsequent phases of the cell cycle, as well as the temporal evolution of the different cell numbers. Our model takes into account the dividing apical progenitors (AP) engaged into neurogenesis, both neurogenic and proliferative IPs, and the newborn neurons. The transfer rates from one population to another are subject to the mode of division (symmetric, asymmetric, neurogenic) and may be time-varying. The model outputs have been successfully fitted to experimental cell numbers from mouse embryos at different stages of cortical development, taking into account IPs and neurons, in order to adjust the numerical parameters. Applying the model to a mouse mutant for Ftm/Rpgrip1l, a gene involved in human ciliopathies with severe brain abnormalities, has revealed a shortening of the neurogenic period associated with an increased influx of newborn IPs from apical progenitors at mid-neurogenesis. Additional information have been provided on cell kinetics, such as the mitotic and S phase indexes, and neurogenic fraction. Our model can be used to study other mouse mutants with cortical neurogenesis defects and can be adapted to study the importance of progenitor dynamics in cortical evolution and human diseases.

#### Advances in computational modeling approaches of pituitary gonadotropin signaling

Participants : Frédérique Clément [correspondant] , Romain Yvinec [INRA] .

Work in collaboration with Pascale Crépieux, Anne Poupon and Éric Reiter (INRA). We have reviewed thoroughly the state-of-the-art in computational modeling approaches of pituitary gonadotropin signaling [30]. Pituitary gonadotropins play an essential and pivotal role in the control of human and animal reproduction within the hypothalamic-pituitary-gonadal (HPG) axis. The computational modeling of pituitary gonadotropin signaling encompasses phenomena of different natures such as the dynamic encoding of gonadotropin secretion, and the intracellular cascades triggered by gonadotropin binding to their cognate receptors, resulting in a variety of biological outcomes. We have overviewed historical and ongoing issues in modeling and data analysis related to gonadotropin secretion in the field of both physiology and neuro-endocrinology. We have mentioned the different mathematical formalisms involved, their interest and limits. We have discussed open statistical questions in signal analysis associated with key endocrine issues. We have also reviewed recent advances in the modeling of the intracellular pathways activated by gonadotropins, which yields promising development for innovative approaches in drug discovery. The greatest challenge to be tackled in computational modeling of pituitary gonadotropin signaling is the embedding of gonadotropin signaling within its natural multiscale environment, from the single cell level, to the organic and whole HPG level. The development of modeling approaches of G protein-coupled receptor signaling, together with multicellular systems biology may lead to unexampled mechanistic understanding with critical expected fallouts in the therapeutic management of reproduction.

#### Structured cell population dynamics applied to the early development of ovarian follicles

Participants : Frédérique Clément, Frédérique Robin [correspondant] , Romain Yvinec [INRA] .

The ovarian follicles are the basic anatomical and functional units of the ovaries, which are renewed from a quiescent pool all along reproductive life. Follicular development involves a finely tuned sequence of growth and maturation processes, involving complex cell dynamics. Understanding follicular development is a crucial issue for the management of reproduction in a clinical or breeding context, and for the preservation of endangered species. In their early stages of development, ovarian follicles are made up of a germ cell (oocyte), whose diameter increases steadily, and of surrounding proliferating somatic cells, which are layered in a globally spherical and compact structure. We have designed a modeling approach dedicated to the initiation phase of follicle development. The initiation phase is described by joint stochastic dynamics accounting for cell shape transitions (from a flattened to a cuboidal shape) and proliferation of reshaped cells. We have then derived the mean time elapsed before all cells have changed shapes and the corresponding increment in the total cell number, which is fitted to experimental data retrieved from primordial follicles (single layered follicle with only flattened cells) and primary follicles (single layered follicles with only cuboidal cells).

#### Newton-Krylov method for computing the cyclic steady states of evolution problems in non-linear mechanics

Participants : Ustim Khristenko, Patrick Le Tallec [correspondant] .

This work is focused on the Newton‐Krylov technique for computing the steady cyclic states of evolution problems in nonlinear mechanics with space‐time periodicity conditions. This kind of problems can be faced, for instance, in the modeling of a rolling tire with a periodic tread pattern, where the cyclic state satisfies “rolling” periodicity condition, including shifts both in time and space. The Newton‐Krylov method is a combination of a Newton nonlinear solver with a Krylov linear solver, looking for the initial state, which provides the space‐time periodic solution. The convergence of the Krylov iterations is proved to hold in presence of an adequate preconditioner. After preconditioning, the Newton‐Krylov method can be also considered as an observer‐controller method, correcting the transient solution of the initial value problem after each period. Using information stored while computing the residual, the Krylov solver computation time becomes negligible with respect to the residual computation time. The method has been analyzed and tested on academic applications and compared with the standard evolution (fixed point) method. Finally, it has been implemented into the Michelin industrial code, applied to a full 3D rolling tire model.

#### Delayed feedback control method for computing the cyclic steady states of evolution problems

Participants : Ustim Khristenko, Patrick Le Tallec [correspondant] .

This work is focused on fast techniques for computing the cyclic steady states of evolution problems in non-linear mechanics with space–time periodicity conditions. In industrial applications, in order to avoid the inversion of very large matrices, such a cyclic solution is usually computed as an asymptotic limit of the associated initial value problem with arbitrary initial data. However, when the relaxation time is high, convergence to the limit cycle can be very slow. In such cases nonetheless, one is not interested in the transient solution, but only in a fast access to the limit cycle. Thus, in this work we modify the problem, introducing the time-delayed feedback control, which is widely used for stabilization of unstable periodic orbits. In our framework it is applied to an initially stable system in order to accelerate its convergence to the limit cycle. Moreover, the control term, based on the space–time periodicity error, includes both shifts in time and in space. Our main result is the optimal form of the control term for a very general class of linear evolution problems, providing the fastest convergence to the cyclic solution, which has been further extended and studied in the non-linear case. Efficiency of the method increases with the problem’s relaxation time. The method has been tested using academic applications and compared to the non-controlled asymptotic convergence as well as to the Newton–Krylov shooting algorithm. Finally, the method has been implemented into the Michelin industrial code, applied to a full 3D rolling tyre model.