A nonlinear elastic description of cell preferential orientations over a stretched substrate

The active response of cells to mechanical cues due to their interaction with the environment has been of increasing interest, since it is involved in many physiological phenomena, pathologies, and in tissue engineering. In particular, several experiments have shown that, if a substrate with overlying cells is cyclically stretched, they will reorient to reach a well-defined angle between their major axis and the main stretching direction. Recent experimental findings, also supported by a linear elastic model, indicated that the minimization of an elastic energy might drive this reorientation process. Motivated by the fact that a similar behaviour is observed even for high strains, in this paper we address the problem in the framework of finite elasticity, in order to study the presence of nonlinear effects. We find that, for a very large class of constitutive orthotropic models and with very general assumptions, there is a single linear relationship between a parameter describing the biaxial deformation and cos^(2) theta(eq), where theta(eq) is the orientation angle of the cell, with the slope of the line depending on a specific combination of four parameters that characterize the nonlinear constitutive equation. We also study the effect of introducing a further dependence of the energy on the anisotropic invariants related to the square of the Cauchy-Green strain tensor. This leads to departures from the linear relationship mentioned above, that are again critically compared with experimental data

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

Mathematical modelling of growth, reorganisation and active response in cells and tissues

The understanding of biological systems like cells and tissues is increasingly taking advantage of tools from quantitative sciences, which can provide powerful instruments to unravel complex mechanisms. In this respect, the emerging field of mechanobiology, that aims at analysing how mechanics affects the cellular and sub-cellular processes, represents a prominent example in which a combination of efforts from several disciplines is fundamental. The contribution of mathematical models to the description of biomedical phenomena can provide a notable support to the research process: indeed, they can be fruitfully employed to reproduce physiological and pathological conditions in silico, and to perform simulations to support clinical observations. Stimulated by these facts, in this Thesis we introduce some models to capture reorganisation, growth, and active processes in cells and tissues, with particular emphasis on their mechanical behaviour. First of all, we deal with the response of cells to external mechanical stimuli, motivated by experimental evidence showing that cells are able to reorganise their cytoskeleton as a reaction to external forces or deformations. Indeed, if cells are placed on a substrate that is cyclically stretched, a reorientation of the cytoskeletal fibres is observed, until a stable configuration is reached. To get insight into such a reorganisation process, which is relevant in tissue engineering and in the understanding of some diseases, we propose different types of models grounded on Continuum Mechanics. After a review of the experimental and modelling literature, we employ tools from nonlinear elasticity, active remodelling, and linear viscoelasticity to capture some relevant experimental observations. We find that strain energies belonging to a very general class all give rise to the same preferential orientations of cells on two-dimensional substrates, corresponding to the observed ones. Moreover, a remodelling framework for an anisotropic material with two fibre families is introduced and applied to the problem of cytoskeletal alignment. Viscoelastic effects are then considered to capture the effect of the deformation frequency on the cell realignment process. Then, we consider another problem related to the cellular response to mechanical stimuli, which is the active contractility of axons. In fact, experimental evidence suggests that the axonal cortex, i.e., the external coating of axons, is able to actively contract and to exert compression on the inner part. This capability seems related to the active regulation of the axon diameter which is observed in some experiments. We describe these phenomena by following an active strain approach, in which both the circumferential and axial contractility of the axonal cortex are considered. A model is derived on a thermodynamically consistent basis and used to simulate the stretching of axons and drug-induced alterations of their cytoskeletal structure, showing a good agreement with experiments. Finally, at the tissue scale, we address the problem of providing a mechanical description of brain tumour growth inside the brain. In fact, the effect of solid stresses in addition to fluid pressure has been proved to be harmful for patients. These negative repercussions are also amplified in brain tissue, which is extremely soft and confined by the skull. To study these issues, we propose a mathematical model of tumour growth based on mixture theory, to account for solid and fluid components, and morphoelasticity, to describe growth-related distortions. Both the healthy brain tissue and the tumour are treated as hyperelastic solids, so as to quantify the displacement and stress induced by cancer growth. Moreover, we perform simulations on a realistic brain geometry, reconstructed from patient-specific data, to underline the importance of a detailed mechanical description of brain tumour growth

Cell orientation under stretch: A review of experimental findings and mathematical modelling

The key role of electro-chemical signals in cellular processes had been known for many years, but more recently the interplay with mechanics has been put in evidence and attracted substantial research interests. Indeed, the sensitivity of cells to mechanical stimuli coming from the microenvironment turns out to be relevant in many biological and physiological circumstances. In particular, experimental evidence demonstrated that cells on elastic planar substrates undergoing periodic stretches, mimicking native cyclic strains in the tissue where they reside, actively reorient their cytoskeletal stress fibres. At the end of the realignment process, the cell axis forms a certain angle with the main stretching direction. Due to the importance of a deeper understanding of mechanotransduction, such a phenomenon was studied both from the experimental and the mathematical modelling point of view. The aim of this review is to collect and discuss both the experimental results on cell reorientation and the fundamental features of the mathematical models that have been proposed in the literature

IDeS Method Applied to an Innovative Motorbike—Applying Topology Optimization and Augmented Reality

This study is on the conception of the DS700 HYBRID project by the application of the Industrial Design Structure method (IDeS), which applies different tools sourced from engineering and style departments, including QFD and SDE, used to create the concept of a hybrid motorbike that could reach the market in the near future. SDE is an engineering approach for the design and development of industrial design projects, and it finds important applications in the automotive sector. In addition, analysis tools such as QFD, comprising benchmarking and top-flop analysis are carried out to maximize the creative process. The key characteristics of the bike and the degree of innovation are identified and outlined, the market segment is identified, and the stylistic trends that are most suitable for a naked motorbike of the future are analyzed. In the second part the styling of each superstructure and of all the components of the vehicle is carried out. Afterwards the aesthetics and engineering perspectives are accounted for to complete the project. This is achieved with modelling and computing tools such as 3D CAD, visual renderings, and FEM simulations, and virtual prototyping thanks to augmented reality (AR), and finally physical prototyping with the use of additive manufacturing (AM). The result is a product conception able to compete in the present challenging market, with a design that is technically feasible and also reaches new lightness targets for efficiency

Orbital Desmoid-Type Fibromatosis: A Case Report and Literature Review

Purpose: Desmoid-type fibromatosis is a benign fibrous neoplasia originating from connective tissue, fascial planes, and musculoaponeurotic structures of the muscles. Currently, there is no evidence-based treatment approach available for desmoid fibromatosis. In this article, a case of a patient in the pediatric age affected by desmoid fibromatosis localized in the orbit is presented. The aim of the article is to describe this unusual and rare location for the desmoid fibromatosis and outline the principle phases in the decision-making process and the therapeutic alternatives for a patient affected by desmoid fibromatosis. Methods: The protocol of this review included study objectives, search strategy, and selection criteria. The primary end point of this study was to analyze the head and neck desmoid fibromatosis. The secondary end point was to identify the available therapies and assess their specific indications. Results: The mean age of patients was 18.9 years ranging from 0 to 66, and 52% were female. A bimodal age distribution was observed, and two age peaks were identified: 0-14 years (57%) and 28-42 years (18%). The most common involved areas were the mandible (25%) followed by the neck (21%). In 86% of the cases, the treatment was the surgical resection of the disease, and only in 5% of the cases, the surgical resection was followed by adjuvant radiotherapy. Conclusion: The orbital location is extremely rare, especially in the pediatric population. The management of desmoid fibromatosis is based on the function preservation and the maintenance of a good quality of life, but in case of symptomatic patients or aggressive course of the disease or risk of functional damages, the surgical approach may be considered. Therapeutic alternatives to surgical resection are radiotherapy and systemic therapy

Indoleamine 2,3-dioxygenase (IDO) enzyme links innate immunity and altered T-cell differentiation in Non-ST segment elevation acute coronary syndrome

Atherosclerosis is a chronic inflammatory disease characterized by a complex interplay between innate and adaptive immunity. Dendritic cells (DCs) play a key role in T-cell activation and regulation by promoting a tolerogenic environment through the expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme involved in tryptophan catabolism. IDO expression and activity was analyzed in monocytes derived DCs (MDDCs) from non-ST segment elevation myocardial infarction (NSTEMI) patients, stable angina (SA) patients and healthy controls (HC) by real-time quantitative polymerase chain reaction (RT-qPCR) before and after in vitro maturation with lipopolysaccharide (LPS). The amount of tryptophan catabolite; kynurenine; was evaluated in the culture supernatants of mature-MDDCs by ELISA assay. Autologous mixed lymphocyte reaction (MLR) between mature-MDDCs and na\uc3\uafve T-cells was carried out to study the differentiation towards T-helper 1 (Th1) and induced regulatory T-cells (iTreg). Analysis of IDO mRNA transcripts in mature-MDDCs revealed a significant reduction in cells isolated from NSTEMI (625.0 \uc2\ub1 128.2; mean \uc2\ub1 SEM) as compared with those from SA (958.5 \uc2\ub1 218.3; p = 0.041) and from HC (1183.6 \uc2\ub1 231.6; p = 0.034). Furthermore; the concentration of kynurenine was lower in NSTEMI patients (2.78 \uc2\ub1 0.2) and SA (2.98 \uc2\ub1 0.25) as compared with HC (5.1 \uc2\ub1 0.69 ng/mL; p = 0.002 and p = 0.016; respectively). When IDO-competent mature-MDDCs were co-cultured with allogeneic na\uc3\uafve T-cells, the ratio between the percentage of generated Th1 and iTreg was higher in NSTEMI (4.4 \uc2\ub1 2.9) than in SA (1.8 \uc2\ub1 0.6; p = 0.056) and HC (0.9 \uc2\ub1 0.3; p = 0.008). In NSTEMI, the tolerogenic mechanism of the immune response related to IDO production by activated MDDCs is altered, supporting their role in T-cell dysregulation