Pasquale Ciarletta

Morpho-elasticity of intestinal villi

Villi are ubiquitous structures in the intestine of all vertebrates, originating from the embryonic development of the epithelial mucosa. Their morphogenesis has similar stages in living organisms but different forming mechanisms. In this work, we model the emergence of the bi-dimensional undulated patterns in the intestinal mucosa from which villi start to elongate. The embryonic mucosa is modelled as a growing thick-walled cylinder, and its mechanical behaviour is described using an hyperelastic constitutive model, which also accounts for the anisotropic characteristics of the reinforcing fibres at the microstructural level. The occurrence of surface undulations is investigated using a linear stability analysis based on the theory of incremental deformations superimposed on a finite deformation. The Stroh formulation of the incremental boundary value problem is derived, and a numerical solution procedure is implemented for calculating the growth thresholds of instability. The numerical results are finally discussed with respect to different growth and materials properties. In conclusion, we demonstrate that the emergence of intestinal villi in embryos is triggered by a differential growth between the mucosa and the mesenchymal tissues. The proposed model quantifies how both the geometrical and the mechanical properties of the mucosa drive the formation of previllous structures in embryos.

Branching instability in expanding bacterial colonies

Self-organization in developing living organisms relies on the capability of cells to duplicate and perform a collective motion inside the surrounding environment. Chemical and mechanical interactions coordinate such a cooperative behaviour, driving the dynamical evolution of the macroscopic system. In this work, we perform an analytical and computational analysis to study pattern formation during the spreading of an initially circular bacterial colony on a Petri dish. The continuous mathematical model addresses the growth and the chemotactic migration of the living monolayer, together with the diffusion and consumption of nutrients in the agar. The governing equations contain four dimensionless parameters, accounting for the interplay among the chemotactic response, the bacteria–substrate interaction and the experimental geometry. The spreading colony is found to be always linearly unstable to perturbations of the interface, whereas branching instability arises in finite-element numerical simulations. The typical length scales of such fingers, which align in the radial direction and later undergo further branching, are controlled by the size parameters of the problem, whereas the emergence of branching is favoured if the diffusion is dominant on the chemotaxis. The model is able to predict the experimental morphologies, confirming that compact (resp. branched) patterns arise for fast (resp. slow) expanding colonies. Such results, while providing new insights into pattern selection in bacterial colonies, may finally have important applications for designing controlled patterns.

Buckling of a coated elastic half-space when the coating and substrate have similar material properties

This study investigates the buckling of a uni-axially compressed neo-Hookean thin film bonded to a neo-Hookean substrate. Previous studies have shown that the elastic bifurcation is supercritical if r≡μf/μs>1.74 and subcritical if r<1.74, where μf and μs are the shear moduli of the film and substrate, respectively. Moreover, existing numerical simulations of the fully nonlinear post-buckling behaviour have all been focused on the regime r>1.74. In this paper, we consider instead a subset of the regime r<1.74, namely when r is close to unity. Four near-critical regimes are considered. In particular, it is shown that, when r>1 and the stretch is greater than the critical stretch (the subcritical regime), there exists a localized solution that arises as the limit of modulated periodic solutions with increasingly longer and longer decaying tails. The evolution of each modulated periodic solution is followed as r is decreased, and it is found that there exists a critical value of r at which the deformation gradient develops a discontinuity and the solution becomes a static shock. The semi-analytical results presented could help future numerical simulations of the fully nonlinear post-buckling behaviour.

Towards the Personalized Treatment of Glioblastoma: Integrating Patient-Specific Clinical Data in a Continuous Mechanical Model

Glioblastoma multiforme (GBM) is the most aggressive and malignant among brain tumors. In addition to uncontrolled proliferation and genetic instability, GBM is characterized by a diffuse infiltration, developing long protrusions that penetrate deeply along the fibers of the white matter. These features, combined with the underestimation of the invading GBM area by available imaging techniques, make a definitive treatment of GBM particularly difficult. A multidisciplinary approach combining mathematical, clinical and radiological data has the potential to foster our understanding of GBM evolution in every single patient throughout his/her oncological history, in order to target therapeutic weapons in a patient-specific manner. In this work, we propose a continuous mechanical model and we perform numerical simulations of GBM invasion combining the main mechano-biological characteristics of GBM with the micro-structural information extracted from radiological images, i.e. by elaborating patient-specific Diffusion Tensor Imaging (DTI) data. The numerical simulations highlight the influence of the different biological parameters on tumor progression and they demonstrate the fundamental importance of including anisotropic and heterogeneous patient-specific DTI data in order to obtain a more accurate prediction of GBM evolution. The results of the proposed mathematical model have the potential to provide a relevant benefit for clinicians involved in the treatment of this particularly aggressive disease and, more importantly, they might drive progress towards improving tumor control and patient’s prognosis.

Mechano-transduction in tumour growth modelling

The evolution of biological systems is strongly influenced by physical factors, such as applied forces, geometry or the stiffness of the micro-environment. Mechanical changes are particularly important in solid tumour development, as altered stromal-epithelial interactions can provoke a persistent increase in cytoskeletal tension, driving the gene expression of a malignant phenotype. In this work, we propose a novel multi-scale treatment of mechano-transduction in cancer growth. The avascular tumour is modelled as an expanding elastic spheroid, whilst growth may occur both as a volume increase and as a mass production within a cell rim. Considering the physical constraints of an outer healthy tissue, we derive the thermo-dynamical requirements for coupling growth rate, solid stress and diffusing biomolecules inside a heterogeneous tumour. The theoretical predictions successfully reproduce the stress-dependent growth curves observed by in vitro experiments on multicellular spheroids.Graphical abstract

Initial stress symmetry and its applications in elasticity

An initial stress within a solid can arise to support external loads or from processes such as thermal expansion in inert matter or growth and remodelling in living materials. For this reason, it is useful to develop a mechanical framework of initially stressed solids irrespective of how this stress formed. An ideal way to do this is to write the free energy density Ψ in terms of initial stress τ and the elastic deformation gradient F, so we write Ψ=Ψ(F,τ). In this paper, we present a new constitutive condition for initially stressed materials, which we call the initial stress symmetry (ISS). We focus on two consequences of this condition. First, we examine how ISS restricts the possible choices of free energy densities Ψ=Ψ(F,τ) and present two examples of Ψ that satisfy the ISS. Second, we show that the initial stress can be derived from the Cauchy stress and the elastic deformation gradient. To illustrate, we take an example from biomechanics and calculate the optimal Cauchy stress within an artery subjected to internal pressure. We then use ISS to derive the optimal target residual stress for the material to achieve after remodelling, which links nicely with the notion of homeostasis.

Morphology of residually stressed tubular tissues: Beyond the elastic multiplicative decomposition

Abstract Many interesting shapes appearing in the biological world are formed by the onset of mechanical instability. In this work we consider how the build-up of residual stress can cause a solid to buckle. In all past studies a fictitious (virtual) stress-free state was required to calculate the residual stress. In contrast, we use a model which is simple and allows the prescription of any residual stress field. We specialize the analysis to an elastic tube subject to a two-dimensional residual stress, and find that incremental wrinkles can appear on its inner or its outer face, depending on the location of the highest value of the residual hoop stress. We further validate the predictions of the incremental theory with finite element simulations, which allow us to go beyond this threshold and predict the shape, number and amplitude of the resulting creases.

Shear instability in skin tissue

Partial funding by the European Community grant ERG-256605, FP7 program, and by the Hardiman Scholarship programme at the National University of Ireland Galway to the first and third authors, respectively.

Solid Tumors Are Poroelastic Solids with a Chemo-mechanical Feedback on Growth

The experimental evidence that a feedback exists between growth and stress in tumors poses challenging questions. First, the rheological properties (the “constitutive equations”) of aggregates of malignant cells are still a matter of debate. Secondly, the feedback law (the “growth law”) that relates stress and mitotic–apoptotic rate is far to be identified. We address these questions on the basis of a theoretical analysis of in vitro and in vivo experiments that involve the growth of tumor spheroids. We show that solid tumors exhibit several mechanical features of a poroelastic material, where the cellular component behaves like an elastic solid. When the solid component of the spheroid is loaded at the boundary, the cellular aggregate grows up to an asymptotic volume that depends on the exerted compression. Residual stress shows up when solid tumors are radially cut, highlighting a peculiar tensional pattern. By a novel numerical approach we correlate the measured opening angle and the underlying residual stress in a sphere. The features of the mechanobiological system can be explained in terms of a feedback of mechanics on the cell proliferation rate as modulated by the availability of nutrient, that is radially damped by the balance between diffusion and consumption. The volumetric growth profiles and the pattern of residual stress can be theoretically reproduced assuming a dependence of the target stress on the concentration of nutrient which is specific of the malignant tissue.

Torsion instability of soft solid cylinders

The application of pure torsion to a long and thin cylindrical rod is known to provoke a twisting instability, evolving from an initial kink to a knot. In the torsional parallel-plate rheometry of stubby cylinders, the geometrical constraints impose zero displacement of the axis of the cylinder, preventing the occurrence of such twisting instability. Under these experimental conditions, wrinkles occur on the cylinders surface at a given critical angle of torsion. Here we investigate this subclass of elastic instability-which we call torsion instability-of soft cylinders subject to a combined finite axial stretch and torsion, by applying the theory of incremental elastic deformation superimposed on finite strains. We formulate the incremental boundary elastic problem in the Stroh differential form, and use the surface impedance method to build a robust numerical procedure for deriving the marginal stability curves. We present the results for a Mooney-Rivlin material and study the influence of the material parameters on the elastic bifurcation.