A theoretical analysis of the scale separation in a model to predict solid tumour growth.

Solid tumour growth depends on a host of factors which affect the cell life cycle and extracellular matrix vascularization that leads to a favourable environment. The whole solid tumour can either grow or wither in response to the action of the immune system and therapeutics. A personalised mathematical model of such behaviour must consider both the intra- and inter-cellular dynamics and the mechanics of the solid tumour and its microenvironment. However, such wide range of spatial and temporal scales can hardly be modelled in a single model, and require the so-called multiscale models, defined as orchestrations of single-scale component models, connected by relation models that transform the data for one scale to another. While multiscale models are becoming common, there is a well-established engineering approach to the definition of the scale separation, e.g., how the spatiotemporal continuum is split in the various component models. In most studies scale separation is defined as natural, linked to anatomical concepts such as organ, tissue, or cell; but these do not provide reliable definition of scales: for examples skeletal organs can be as large as 500 mm (femur), or as small as 3 mm (stapes). Here we apply a recently proposed scale-separation approach based on the actual experimental and computational limitations to a patient-specific model of the growth of neuroblastoma. The resulting multiscale model can be properly informed with the available experimental data and solved in a reasonable timeframe with the available computational resources.

Confined Cell Migration and Asymmetric Hydraulic Environments to Evaluate the Metastatic Potential of Cancer Cells.

Metastasis, a hallmark of cancer development, is also the leading reason for most cancer-related deaths. Furthermore, cancer cells are highly adaptable to micro-environments and can migrate along pre-existing channel-like tracks of anatomical structures. However, more representative three-dimensional models are required to reproduce the heterogeneity of metastatic cell migration in vivo to further understand the metastasis mechanism and develop novel therapeutic strategies against it. Here, we designed and fabricated different microfluidic-based devices that recreate confined migration and diverse environments with asymmetric hydraulic resistances. Our results show different migratory potential between metastatic and nonmetastatic cancer cells in confined environments. Moreover, although nonmetastatic cells have not been tested against barotaxis due to their low migration capacity, metastatic cells present an enhanced preference to migrate through the lowest resistance path, being sensitive to barotaxis. This device, approaching the study of metastasis capability based on confined cell migration and barotactic cell decisions, may pave the way for the implementation of such technology to determine and screen the metastatic potential of certain cancer cells.

Computational modelling of the mechanical behaviour of protein-based hydrogels.

Protein-based hydrogels have been extensively studied in the field of biomaterials given their ability to mimic living tissues and their special resemblance to the extracellular matrix. Despite this, the methods used for the control of mechanical properties of hydrogels are very limited, focusing mainly on their elasticity, with an often unrealistic characterization of mechanical properties such as extensibility, stiffness and viscoelasticity. Being able to control these properties is essential for the development of new biomaterials, since it has been demonstrated that mechanical properties affect cell behaviour and biological processes. To better understand the mechanical behaviour of these biopolymers, a computational model is here developed to characterize the mechanical behaviour of two different protein-based hydrogels. Strain-stress tests and stress-relaxation tests are evaluated computationally and compared to the results obtained experimentally in a previous work. To achieve this goal the Finite Element Method is used, combining hyperelastic and viscoelastic models. Different hyperelastic constitutive models (Mooney-Rivlin, Neo-Hookean, first and third order Ogden, and Yeoh) are proposed to estimate the mechanical properties of the protein-based hydrogels by least-square fitting of the in-vitro uniaxial test results. Among these models, the first order Ogden model with a viscoelastic model defined in Prony parameters better reproduces the strain-stress response and the change of stiffness with strain observed in the in-vitro tests.

Fluid flow to mimic organ function in 3D in vitro models.

Many different strategies can be found in the literature to model organ physiology, tissue functionality, and disease in vitro; however, most of these models lack the physiological fluid dynamics present in vivo. Here, we highlight the importance of fluid flow for tissue homeostasis, specifically in vessels, other lumen structures, and interstitium, to point out the need of perfusion in current 3D in vitro models. Importantly, the advantages and limitations of the different current experimental fluid-flow setups are discussed. Finally, we shed light on current challenges and future focus of fluid flow models applied to the newest bioengineering state-of-the-art platforms, such as organoids and organ-on-a-chip, as the most sophisticated and physiological preclinical platforms.

Tumour growth: An approach to calibrate parameters of a multiphase porous media model based on in vitro observations of Neuroblastoma spheroid growth in a hydrogel microenvironment.

To unravel processes that lead to the growth of solid tumours, it is necessary to link knowledge of cancer biology with the physical properties of the tumour and its interaction with the surrounding microenvironment. Our understanding of the underlying mechanisms is however still imprecise. We therefore developed computational physics-based models, which incorporate the interaction of the tumour with its surroundings based on the theory of porous media. However, the experimental validation of such models represents a challenge to its clinical use as a prognostic tool. This study combines a physics-based model with in vitro experiments based on microfluidic devices used to mimic a three-dimensional tumour microenvironment. By conducting a global sensitivity analysis, we identify the most influential input parameters and infer their posterior distribution based on Bayesian calibration. The resulting probability density is in agreement with the scattering of the experimental data and thus validates the proposed workflow. This study demonstrates the huge challenges associated with determining precise parameters with usually only limited data for such complex processes and models, but also demonstrates in general how to indirectly characterise the mechanical properties of neuroblastoma spheroids that cannot feasibly be measured experimentally.

Unravelling cell migration: defining movement from the cell surface.

Cell motility is essential for life and development. Unfortunately, cell migration is also linked to several pathological processes, such as cancer metastasis. Cells' ability to migrate relies on many actors. Cells change their migratory strategy based on their phenotype and the properties of the surrounding microenvironment. Cell migration is, therefore, an extremely complex phenomenon. Researchers have investigated cell motility for more than a century. Recent discoveries have uncovered some of the mysteries associated with the mechanisms involved in cell migration, such as intracellular signaling and cell mechanics. These findings involve different players, including transmembrane receptors, adhesive complexes, cytoskeletal components , the nucleus, and the extracellular matrix. This review aims to give a global overview of our current understanding of cell migration.

A new 3D finite element-based approach for computing cell surface tractions assuming nonlinear conditions.

Advances in methods for determining the forces exerted by cells while they migrate are essential for attempting to understand important pathological processes, such as cancer or angiogenesis, among others. Precise data from three-dimensional conditions are both difficult to obtain and manipulate. For this purpose, it is critical to develop workflows in which the experiments are closely linked to the subsequent computational postprocessing. The work presented here starts from a traction force microscopy (TFM) experiment carried out on microfluidic chips, and this experiment is automatically joined to an inverse problem solver that allows us to extract the traction forces exerted by the cell from the displacements of fluorescent beads embedded in the extracellular matrix (ECM). Therefore, both the reconstruction of the cell geometry and the recovery of the ECM displacements are used to generate the inputs for the resolution of the inverse problem. The inverse problem is solved iteratively by using the finite element method under the hypothesis of finite deformations and nonlinear material formulation. Finally, after mathematical postprocessing is performed, the traction forces on the surface of the cell in the undeformed configuration are obtained. Therefore, in this work, we demonstrate the robustness of our computational-based methodology by testing it under different conditions in an extreme theoretical load problem and then by applying it to a real case based on experimental results. In summary, we have developed a new procedure that adds value to existing methodologies for solving inverse problems in 3D, mainly by allowing for large deformations and not being restricted to any particular material formulation. In addition, it automatically bridges the gap between experimental images and mechanical computations.

Multiscale modeling of bone tissue mechanobiology.

Mechanical environment has a crucial role in our organism at the different levels, ranging from cells to tissues and our own organs. This regulatory role is especially relevant for bones, given their importance as load-transmitting elements that allow the movement of our body as well as the protection of vital organs from load impacts. Therefore bone, as living tissue, is continuously adapting its properties, shape and repairing itself, being the mechanical loads one of the main regulatory stimuli that modulate this adaptive behavior. Here we review some key results of bone mechanobiology from computational models, describing the effect that changes associated to the mechanical environment induce in bone response, implant design and scaffold-driven bone regeneration.