Utilising an in silico model to predict outcomes in senescence-driven acute liver injury.

Currently liver transplantation is the only treatment option for liver disease, but organ availability cannot meet patient demand. Alternative regenerative therapies, including cell transplantation, aim to modulate the injured microenvironment from inflammation and scarring towards regeneration. The complexity of the liver injury response makes it challenging to identify suitable therapeutic targets when relying on experimental approaches alone.

Enhancing nanoscale viscoelasticity characterization in bimodal atomic force microscopy.

Polymeric, soft, and biological materials exhibit viscoelasticity, which is a time dependent mechanical response to deformation. Material viscoelasticity emerges from the movement of a material's constituent molecules at the nano- and microscale in response to applied deformation. Therefore, viscoelastic properties depend on the speed at which a material is deformed.

Exploiting in silico modelling to enhance translation of liver cell therapies from bench to bedside.

Cell therapies are emerging as promising treatments for a range of liver diseases but translational bottlenecks still remain including: securing and assessing the safe and effective delivery of cells to the disease site; ensuring successful cell engraftment and function; and preventing immunogenic responses. Here we highlight three therapies, each utilising a different cell type, at different stages in their clinical translation journey: transplantation of multipotent mesenchymal stromal/signalling cells, hepatocytes and macrophages. To overcome bottlenecks impeding clinical progression, we advocate for wider use of mechanistic in silico modelling approaches.

Curvature in Biological Systems: Its Quantification, Emergence, and Implications across the Scales.

Surface curvature both emerges from, and influences the behavior of, living objects at length scales ranging from cell membranes to single cells to tissues and organs. The relevance of surface curvature in biology is supported by numerous experimental and theoretical investigations in recent years. In this review, first, a brief introduction to the key ideas of surface curvature in the context of biological systems is given and the challenges that arise when measuring surface curvature are discussed.

A model-informed approach to assess the risk of immune checkpoint inhibitor-induced autoimmune myocarditis.

Immune checkpoint inhibitors (ICIs), as a novel immunotherapy, are designed to modulate the immune system to attack malignancies. Despite their promising benefits, immune-related adverse events (IRAEs) may occur, and incidences are bound to increase with surging demand of this class of drugs in treating cancer. Myocarditis, although rare compared to other IRAEs, has a significantly higher fatal frequency.

Mathematical modelling of autoimmune myocarditis and the effects of immune checkpoint inhibitors.

Autoimmune myocarditis is a rare, but frequently fatal, side effect of immune checkpoint inhibitors (ICIs), a class of cancer therapies. Despite extensive experimental work on the causes, development and progression of this disease, much still remains unknown about the importance of the different immunological pathways involved. We present a mathematical model of autoimmune myocarditis and the effects of ICIs on its development and progression to either resolution or chronic inflammation.

A Systematically Reduced Mathematical Model for Organoid Expansion.

Organoids are three-dimensional multicellular tissue constructs. When cultured , they recapitulate the structure, heterogeneity, and function of their counterparts. As awareness of the multiple uses of organoids has grown, .

Combining multiple spatial statistics enhances the description of immune cell localisation within tumours.

Digital pathology enables computational analysis algorithms to be applied at scale to histological images. An example is the identification of immune cells within solid tumours. Image analysis algorithms can extract precise cell locations from immunohistochemistry slides, but the resulting spatial coordinates, or point patterns, can be difficult to interpret.

Mathematical modelling reveals cellular dynamics within tumour spheroids.

Tumour spheroids are widely used as an in vitro assay for characterising the dynamics and response to treatment of different cancer cell lines. Their popularity is largely due to the reproducible manner in which spheroids grow: the diffusion of nutrients and oxygen from the surrounding culture medium, and their consumption by tumour cells, causes proliferation to be localised at the spheroid boundary. As the spheroid grows, cells at the spheroid centre may become hypoxic and die, forming a necrotic core.

Predicting Bone Formation in Mesenchymal Stromal Cell-Seeded Hydrogels Using Experiment-Based Mathematical Modeling.

bone formation by mesenchymal stromal cells encapsulated in type-1 collagen hydrogels is demonstrated after a 28-day culture period. Analysis of the hydrogels is carried out by X-ray microcomputed tomography, histology, and immunohistochemistry, which collectively demonstrates that bone formation in the hydrogels was quantifiably proportional to the initial collagen concentration, and subsequently the population density of seeded cells. This was established by varying the initial collagen concentration at a constant cell seeding density (3 × 10 cells/0.

Identifying chondrogenesis strategies for tissue engineering of articular cartilage.

A key step in the tissue engineering of articular cartilage is the chondrogenic differentiation of mesenchymal stem cells (MSCs) into chondrocytes (native cartilage cells). Chondrogenesis is regulated by transforming growth factor- (TGF-), a short-lived cytokine whose effect is prolonged by storage in the extracellular matrix. Tissue engineering applications aim to maximise the yield of differentiated MSCs.

The Fluid Mechanics of Ureteroscope Irrigation.

Purpose: To develop a physical understanding of ureterorenoscopy irrigation, we derive mathematical models from basic physical principles and compare these predictions with the results of benchtop experiments. Mathematical modeling can be used to understand the role of inlet pressure, tip deflection, the presence of working tools, geometric properties of the instruments used, and material properties of the irrigation fluid on resulting flow rate.

Materials And Methods: We develop theoretical models to describe irrigation flow in an idealized setup and compare with benchtop experiments for flow through a straight scope, a scope with a deflected tip, and a scope with a working tool inserted.

Lattice and continuum modelling of a bioactive porous tissue scaffold.

A contemporary procedure to grow artificial tissue is to seed cells onto a porous biomaterial scaffold and culture it within a perfusion bioreactor to facilitate the transport of nutrients to growing cells. Typical models of cell growth for tissue engineering applications make use of spatially homogeneous or spatially continuous equations to model cell growth, flow of culture medium, nutrient transport and their interactions. The network structure of the physical porous scaffold is often incorporated through parameters in these models, either phenomenologically or through techniques like mathematical homogenization.

Inducing chondrogenesis in MSC/chondrocyte co-cultures using exogenous TGF-β: a mathematical model.

The differentiation of mesenchymal stem cells (MSCs) into chondrocytes (native cartilage cells), or chondrogenesis, is a key step in the tissue engineering of articular cartilage, where the motility and high proliferation rate of MSCs used as seed cells are exploited. Chondrogenesis is regulated by transforming growth factor-beta (TGF-β), a short-lived cytokine whose effect is prolonged by storage in the extracellular matrix. Tissue engineering applications require the complete differentiation of an initial population of MSCs, and two common strategies used to achieve this in vitro are (1) co-culture the MSCs with chondrocytes, which constitutively produce TGF-β; or (2) add exogenous TGF-β.

Mathematical modelling of cell layer growth in a hollow fibre bioreactor.

Generating autologous tissue grafts of a clinically useful volume requires efficient and controlled expansion of cell populations harvested from patients. Hollow fibre bioreactors show promise as cell expansion devices, owing to their potential for scale-up. However, further research is required to establish how to specify appropriate hollow fibre bioreactor operating conditions for expanding different cell types.

Mathematical modelling of blood-brain barrier failure and oedema.

Injuries such as traumatic brain injury and stroke can result in increased blood-brain barrier (BBB) permeability. This increase may lead to water accumulation in the brain tissue resulting in vasogenic oedema. Although the initial injury may be localized, the resulting oedema causes mechanical damage and compression of the vasculature beyond the original injury site.

A multiphase model for chemically- and mechanically- induced cell differentiation in a hollow fibre membrane bioreactor: minimising growth factor consumption.

We present a simplified two-dimensional model of fluid flow, solute transport, and cell distribution in a hollow fibre membrane bioreactor. We consider two cell populations, one undifferentiated and one differentiated, with differentiation stimulated either by growth factor alone, or by both growth factor and fluid shear stress. Two experimental configurations are considered, a 3-layer model in which the cells are seeded in a scaffold throughout the extracapillary space (ECS), and a 4-layer model in which the cell-scaffold construct occupies a layer surrounding the outside of the hollow fibre, only partially filling the ECS.

Global contraction or local growth, bleb shape depends on more than just cell structure.

When the plasma membrane of a cell locally delaminates from its actin cortex the membrane is pushed outwards due to the cell׳s internal fluid pressure. The resulting spherical protrusion is known as a bleb. A cell׳s ability to function correctly is highly dependent on the production of such protrusions with the correct size and shape.

Propagation of damage in brain tissue: coupling the mechanics of oedema and oxygen delivery.

Brain tissue swelling, or oedema, is a dangerous consequence of traumatic brain injury and stroke. In particular, a locally swollen region can cause the injury to propagate further through the brain: swelling causes mechanical compression of the vasculature in the surrounding tissue and so can cut off that tissue's oxygen supply. We use a triphasic mathematical model to investigate this propagation, and couple tissue mechanics with oxygen delivery.

Multiphase modelling of the effect of fluid shear stress on cell yield and distribution in a hollow fibre membrane bioreactor.

We present a simplified two-dimensional model of fluid flow, nutrient transport and cell distribution in a hollow fibre membrane bioreactor, with the aim of exploring how fluid flow can be used to control the distribution and yield of a cell population which is sensitive to both fluid shear stress and nutrient concentration. The cells are seeded in a scaffold in a layer on top of the hollow fibre, only partially occupying the extracapillary space. Above this layer is a region of free-flowing fluid which we refer to as the upper fluid layer.

Optimising cell aggregate expansion in a perfused hollow fibre bioreactor via mathematical modelling.

The need for efficient and controlled expansion of cell populations is paramount in tissue engineering. Hollow fibre bioreactors (HFBs) have the potential to meet this need, but only with improved understanding of how operating conditions and cell seeding strategy affect cell proliferation in the bioreactor. This study is designed to assess the effects of two key operating parameters (the flow rate of culture medium into the fibre lumen and the fluid pressure imposed at the lumen outlet), together with the cell seeding distribution, on cell population growth in a single-fibre HFB.

Evaluation of the growth environment of a hydrostatic force bioreactor for preconditioning of tissue-engineered constructs.

Bioreactors have been widely acknowledged as valuable tools to provide a growth environment for engineering tissues and to investigate the effect of physical forces on cells and cell-scaffold constructs. However, evaluation of the bioreactor environment during culture is critical to defining outcomes. In this study, the performance of a hydrostatic force bioreactor was examined by experimental measurements of changes in dissolved oxygen (O2), carbon dioxide (CO2), and pH after mechanical stimulation and the determination of physical forces (pressure and stress) in the bioreactor through mathematical modeling and numerical simulation.

Is the Donnan effect sufficient to explain swelling in brain tissue slices?

Brain tissue swelling is a dangerous consequence of traumatic injury and is associated with raised intracranial pressure and restricted blood flow. We consider the mechanical effects that drive swelling of brain tissue slices in an ionic solution bath, motivated by recent experimental results that showed that the volume change of tissue slices depends on the ionic concentration of the bathing solution. This result was attributed to the presence of large charged molecules that induce ion concentration gradients to ensure electroneutrality (the Donnan effect), leading to osmotic pressures and water accumulation.

Multiphase modelling of the influence of fluid flow and chemical concentration on tissue growth in a hollow fibre membrane bioreactor.

A 2D model is developed for fluid flow, mass transport and cell distribution in a hollow fibre membrane bioreactor. The geometry of the modelling region is simplified by excluding the exit ports at either end and focusing on the upper half of the central section of the bioreactor. Cells are seeded on a porous scaffold throughout the extracapillary space (ECS), and fluid pumped through the bioreactor via the lumen inlet and/or exit ports.

Cellular blebs: pressure-driven, axisymmetric, membrane protrusions.

Blebs are cellular protrusions that are used by cells for multiple purposes including locomotion. A mechanical model for the problem of pressure-driven blebs based on force and moment balances of an axisymmetric shell model is proposed. The formation of a bleb is initiated by weakening the shell over a small region, and the deformation of the cellular membrane from the cortex is obtained during inflation.