Flattened and Wrinkled Encapsulated Droplets: Shape Morphing Induced by Gravity and Evaporation.

We report surprising morphological changes of suspension droplets (containing class II hydrophobin protein HFBI from Trichoderma reesei in water) as they evaporate with a contact line pinned on a rigid solid substrate. Both pendant and sessile droplets display the formation of an encapsulating elastic film as the bulk concentration of solute reaches a critical value during evaporation, but the morphology of the droplet varies significantly: for sessile droplets, the elastic film ultimately crumples in a nearly flattened area close to the apex while in pendant droplets, circumferential wrinkling occurs close to the contact line. These different morphologies are understood through a gravito-elastocapillary model that predicts the droplet morphology and the onset of shape changes, as well as showing that the influence of the direction of gravity remains crucial even for very small droplets (where the effect of gravity can normally be neglected). The results pave the way to control droplet shape in several engineering and biomedical applications.

Coupling solid and fluid stresses with brain tumour growth and white matter tract deformations in a neuroimaging-informed model.

Brain tumours are among the deadliest types of cancer, since they display a strong ability to invade the surrounding tissues and an extensive resistance to common therapeutic treatments. It is therefore important to reproduce the heterogeneity of brain microstructure through mathematical and computational models, that can provide powerful instruments to investigate cancer progression. However, only a few models include a proper mechanical and constitutive description of brain tissue, which instead may be relevant to predict the progression of the pathology and to analyse the reorganization of healthy tissues occurring during tumour growth and, possibly, after surgical resection. Motivated by the need to enrich the description of brain cancer growth through mechanics, in this paper we present a mathematical multiphase model that explicitly includes brain hyperelasticity. We find that our mechanical description allows to evaluate the impact of the growing tumour mass on the surrounding healthy tissue, quantifying the displacements, deformations, and stresses induced by its proliferation. At the same time, the knowledge of the mechanical variables may be used to model the stress-induced inhibition of growth, as well as to properly modify the preferential directions of white matter tracts as a consequence of deformations caused by the tumour. Finally, the simulations of our model are implemented in a personalized framework, which allows to incorporate the realistic brain geometry, the patient-specific diffusion and permeability tensors reconstructed from imaging data and to modify them as a consequence of the mechanical deformation due to cancer growth.

In Silico Mathematical Modelling for Glioblastoma: A Critical Review and a Patient-Specific Case.

Glioblastoma extensively infiltrates the brain; despite surgery and aggressive therapies, the prognosis is poor. A multidisciplinary approach combining mathematical, clinical and radiological data has the potential to foster our understanding of glioblastoma evolution in every single patient, with the aim of tailoring therapeutic weapons. In particular, the ultimate goal of biomathematics for cancer is the identification of the most suitable theoretical models and simulation tools, both to describe the biological complexity of carcinogenesis and to predict tumor evolution. In this report, we describe the results of a critical review about different mathematical models in neuro-oncology with their clinical implications. A comprehensive literature search and review for English-language articles concerning mathematical modelling in glioblastoma has been conducted. The review explored the different proposed models, classifying them and indicating the significative advances of each one. Furthermore, we present a specific case of a glioblastoma patient in which our recently proposed innovative mechanical model has been applied. The results of the mathematical models have the potential to provide a relevant benefit for clinicians and, more importantly, they might drive progress towards improving tumor control and patient's prognosis. Further prospective comparative trials, however, are still necessary to prove the impact of mathematical neuro-oncology in clinical practice.

Partial differential model of lactate neuro-energetics: analytic results and numerical simulations.

Interfaces play a key role on diseases development because they dictate the energy inflow of nutrients from the surrounding tissues. What is underestimated by existing mathematical models is the biological fact that cells are able to use different resources through nonlinear mechanisms. Among all nutrients, lactate appears to be a sensitive metabolic when talking about brain tumours or neurodegenerative diseases. Here we present a partial differential model to investigate the lactate exchanges between cells and the vascular network in the brain. By extending an existing kinetic model for lactate neuro-energetics, we first provide analytical proofs of the uniqueness and the derivation of precise bounds on the solutions of the problem including diffusion of lactate in a representative volume element comprising the interface between a capillary and cells. We further perform finite element simulations of the model in two test cases, discussing the relevant physical parameters governing the lactate dynamics.

Faraday waves in soft elastic solids.

Recent experiments have observed the emergence of standing waves at the free surface of elastic bodies attached to a rigid oscillating substrate and subjected to critical values of forcing frequency and amplitude. This phenomenon, known as Faraday instability, is now well understood for viscous fluids but surprisingly eluded any theoretical explanation for soft solids. Here, we characterize Faraday waves in soft incompressible slabs using the Floquet theory to study the onset of harmonic and subharmonic resonance eigenmodes. We consider a ground state corresponding to a finite homogeneous deformation of the elastic slab. We transform the incremental boundary value problem into an algebraic eigenvalue problem characterized by the three dimensionless parameters, that characterize the interplay of gravity, capillary and elastic waves. Remarkably, we found that Faraday instability in soft solids is characterized by a harmonic resonance in the physical range of the material parameters. This seminal result is in contrast to the subharmonic resonance that is known to characterize viscous fluids, and opens the path for using Faraday waves for a precise and robust experimental method that is able to distinguish solid-like from fluid-like responses of soft matter at different scales.

Mechano-biological model of glioblastoma cells in response to osmotic stress.

This work investigates the mechano-biological features of cells cultured in monolayers in response to different osmotic conditions. In-vitro experiments have been performed to quantify the long-term effects of prolonged osmotic stresses on the morphology and proliferation capacity of glioblastoma cells. The experimental results highlight that both hypotonic and hypertonic conditions affect the proliferative rate of glioblastoma cells on different cell cycle phases. Moreover, glioblastoma cells in hypertonic conditions display a flattened and elongated shape. The latter effect is explained using a nonlinear elastic model for the single cell. Due to a crossover between the free energy contributions related to the cytosol and the cytoskeletal fibers, a critical osmotic stress determines a morphological transition from a uniformly compressed to an elongated shape.

On the morphological stability of multicellular tumour spheroids growing in porous media.

Multicellular tumour spheroids (MCTSs) are extensively used as in vitro system models for investigating the avascular growth phase of solid tumours. In this work, we propose a continuous growth model of heterogeneous MCTSs within a porous material, taking into account a diffusing nutrient from the surrounding material directing both the proliferation rate and the mobility of tumour cells. At the time scale of interest, the MCTS behaves as an incompressible viscous fluid expanding inside a porous medium. The cell motion and proliferation rate are modelled using a non-convective chemotactic mass flux, driving the cell expansion in the direction of the external nutrients' source. At the early stages, the growth dynamics is derived by solving the quasi-stationary problem, obtaining an initial exponential growth followed by an almost linear regime, in accordance with experimental observations. We also perform a linear-stability analysis of the quasi-static solution in order to investigate the morphological stability of the radially symmetric growth pattern. We show that mechano-biological cues, as well as geometric effects related to the size of the MCTS subdomains with respect to the diffusion length of the nutrient, can drive a morphological transition to fingered structures, thus triggering the formation of complex shapes that might promote tumour invasiveness. The results also point out the formation of a retrograde flow in the MCTS close to the regions where protrusions form, that could describe the initial dynamics of metastasis detachment from the in vivo tumour mass. In conclusion, the results of the proposed model demonstrate that the integration of mathematical tools in biological research could be crucial for better understanding the tumour's ability to invade its host environment.

Tumour angiogenesis as a chemo-mechanical surface instability.

The hypoxic conditions within avascular solid tumours may trigger the secretion of chemical factors, which diffuse to the nearby vasculature and promote the formation of new vessels eventually joining the tumour. Mathematical models of this process, known as tumour angiogenesis, have mainly investigated the formation of the new capillary networks using reaction-diffusion equations. Since angiogenesis involves the growth dynamics of the endothelial cells sprouting, we propose in this work an alternative mechanistic approach, developing a surface growth model for studying capillary formation and network dynamics. The model takes into account the proliferation of endothelial cells on the pre-existing capillary surface, coupled with the bulk diffusion of the vascular endothelial growth factor (VEGF). The thermo-dynamical consistency is imposed by means of interfacial and bulk balance laws. Finite element simulations show that both the morphology and the dynamics of the sprouting vessels are controlled by the bulk diffusion of VEGF and the chemo-mechanical and geometric properties at the capillary interface. Similarly to dendritic growth processes, we suggest that the emergence of tree-like vessel structures during tumour angiogenesis may result from the free boundary instability driven by competition between chemical and mechanical phenomena occurring at different length-scales.

Emerging morphologies in round bacterial colonies: comparing volumetric versus chemotactic expansion.

Biological experiments performed on living bacterial colonies have demonstrated the microbial capability to develop finger-like shapes and highly irregular contours, even starting from an homogeneous inoculum. In this work, we study from the continuum mechanics viewpoint the emergence of such branched morphologies in an initially circular colony expanding on the top of a Petri dish coated with agar. The bacterial colony expansion, based on either a source term, representing volumetric mitotic processes, or a nonconvective mass flux, describing chemotactic expansion, is modeled at the continuum scale. We demonstrate that the front of the colony is always linearly unstable, having similar dispersion curves to the ones characterizing branching instabilities. We also perform finite element simulations, which not only prove the emergence of branching, but also highlight dramatic differences between the two mechanisms of colony expansion in the nonlinear regime. Furthermore, the proposed combination of analytical and numerical analysis allowed studying the influence of different model parameters on the selection of specific patterns. A very good agreement has been found between the resulting simulations and the typical structures observed in biological assays. Finally, this work provides a new interpretation of the emergence of branched patterns in living aggregates, depicted as the results of a complex interplay among chemical, mechanical and size effects.

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.

Mechanically driven branching of bacterial colonies.

A continuum mathematical model with sharp interface is proposed for describing the occurrence of patterns in initially circular and homogeneous bacterial colonies. The mathematical model encapsulates the evolution of the chemical field characterized by a Monod-like uptake term, the chemotactic response of bacteria, the viscous interaction between the colony and the underlying culture medium and the effects of the surface tension at the boundary. The analytical analysis demonstrates that the front of the colony is linearly unstable for a proper choice of the parameters. The simulation of the model in the nonlinear regime confirms the development of fingers with typical wavelength controlled by the size parameters of the problem, whilst the emergence of branches is favored if the diffusion is dominant on the chemotaxis or for high values of the friction parameter. Such results provide new insights on pattern selection in bacterial colonies and may be applied for designing engineered patterns.

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.

Free boundary morphogenesis in living matter.

Morphogenetic theories investigate the creation and the emergence of form in living organisms. A novel approach for studying free boundary problems during morphogenesis is proposed in this work. The presence of mass fluxes inside a biological system is coupled with the local gradient of diffusing morphogens. The contour stability of a growing material is studied using a two-dimensional system model with a rectilinear free border inside a Hele-Shaw cell. Modeling mass transport during morphogenesis allows fixing the velocity at the traveling wave solution as a function of one-dimensionless parameter. Performing a perturbation of the free boundary, the dispersion relation is derived in an implicit form. Although both the velocity of the moving front and the surface tension act as stabilizing effects at small wavelengths, the dispersion diagrams show that the rectilinear border is always unstable at large wavelengths. Further applications of this model can help give insights into a number of free boundary problems in biological systems.

Morphological changes in early melanoma development: influence of nutrients, growth inhibitors and cell-adhesion mechanisms.

Current diagnostic methods for skin cancers are based on some morphological characteristics of the pigmented skin lesions, including the geometry of their contour. The aim of this article is to model the early growth of melanoma accounting for the biomechanical characteristics of the tumor micro-environment, and evaluating their influence on the tumor morphology and its evolution. The spatial distribution of tumor cells and diffusing molecules are explicitly described in a three-dimensional multiphase model, which incorporates general cell-to-cell mechanical interactions, a dependence of cell proliferation on contact inhibition, as well as a local diffusion of nutrients and inhibiting molecules. A two-dimensional model is derived in a lubrication limit accounting for the thin geometry of the epidermis. First, the dynamical and spatial properties of planar and circular tumor fronts are studied, with both numerical and analytical techniques. A WKB method is then developed in order to analyze the solution of the governing partial differential equations and to derive the threshold conditions for a contour instability of the growing tumor. A control parameter and a critical wavelength are identified, showing that high cell proliferation, high cell adhesion, large tumor radius and slow tumor growth correlate with the occurrence of a contour instability. Finally, comparing the theoretical results with a large amount of clinical data we show that our predictions describe accurately both the morphology of melanoma observed in vivo and its variations with the tumor growth rate. This study represents a fundamental step to understand more complex microstructural patterns observed during skin tumor growth. Its results have important implications for the improvement of the diagnostic methods for melanoma, possibly driving progress towards a personalized screening.

Stiffening by fiber reinforcement in soft materials: a hyperelastic theory at large strains and its application.

This work defines an incompressible, hyperelastic theory of anisotropic soft materials at finite strains, which is tested by application to the experimental response of fiber-reinforced rubber materials. The experimental characterization is performed using a uniaxial testing device with optical measures of the deformation, using two different reinforcing materials on a ground rubber matrix. In order to avoid non-physical responses of the underlying structural components of the material, the kinematics of the deformation are described using a novel deformation tensor, which ensures physical consistency at large strains. A constitutive relation for incompressible fiber-reinforced materials is presented, while issues of stability and ellipticity for the hyperelastic solution are considered to impose necessary restrictions on the constitutive parameters. The theoretical predictions of the proposed model are compared with the anisotropic experimental responses, showing high fitting accuracy in determining the mechanical parameters of the model. The constitutive theory is suitable to account for the anisotropic response at large compressive strains, opening perspectives for many applications in tissue engineering and biomechanics.

Pseudo-hyperelastic model of tendon hysteresis from adaptive recruitment of collagen type I fibrils.

Understanding the functional relationship between the viscoelasticity and the morphology of soft collagenous tissues is fundamental for many applications in bioengineering science. This work presents a pseudo-hyperelastic constitutive theory aiming at describing the time-dependant hysteretic response of tendons subjected to uniaxial tensile loads. A macroscopic tendon is modeled as a composite homogeneous tissue with the anisotropic reinforcement of collagen type I fibrils. The tissue microstructure is considered as an adaptive network of fibrillar units connected in temporary junctions. The processes of breakage and reformation of active fibrils are thermally activated, and are occurring at random times. An internal softening variable and a dissipation energy function account for the adaptive arrangement of the fibrillar network in the pseudo-hyperelastic model. Cyclic uniaxial tensile tests have been performed in vitro on porcine flexor digital tendons. The theoretical predictions fit accurately the experimental stress-strain data both for the loading and the unloading processes. The hysteresis behavior reflects the improvement in the efficiency and performance of the motion of the muscle-tendon unit at high strain rates. The results of the model demonstrate the microstructural importance of proteoglycans in determining the functional viscoelastic adaptability of the macroscopic tendon.