Modelling the rheology of living cell cytoplasm: poroviscoelasticity and fluid-to-solid transition.

Eukaryotic cell rheology has important consequences for vital processes such as adhesion, migration, and differentiation. Experiments indicate that cell cytoplasm can exhibit both elastic and viscous characteristics in different regimes, while the transport of fluid (cytosol) through the cross-linked filamentous scaffold (cytoskeleton) is reminiscent of mass transfer by diffusion through a porous medium. To gain insights into this complex rheological behaviour, we construct a computational model for the cell cytoplasm as a poroviscoelastic material formulated on the principles of nonlinear continuum mechanics, where we model the cytoplasm as a porous viscoelastic scaffold with an embedded viscous fluid flowing between the pores to model the cytosol. Baseline simulations (neglecting the viscosity of the cytosol) indicate that the system exhibits seven different regimes across the parameter space spanned by the viscoelastic relaxation timescale of the cytoskeleton and the poroelastic diffusion timescale; these regimes agree qualitatively with experimental measurements. Furthermore, the theoretical model also allows us to elucidate the additional role of pore fluid viscosity, which enters the system as a distinct viscous timescale. We show that increasing this viscous timescale hinders the passage of the pore fluid (reducing the poroelastic diffusion) and makes the cytoplasm rheology increasingly incompressible, shifting the phase boundaries between the regimes.

Enhanced perfusion following exposure to radiotherapy: A theoretical investigation.

Tumour angiogenesis leads to the formation of blood vessels that are structurally and spatially heterogeneous. Poor blood perfusion, in conjunction with increased hypoxia and oxygen heterogeneity, impairs a tumour's response to radiotherapy. The optimal strategy for enhancing tumour perfusion remains unclear, preventing its regular deployment in combination therapies. In this work, we first identify vascular architectural features that correlate with enhanced perfusion following radiotherapy, using in vivo imaging data from vascular tumours. Then, we present a novel computational model to determine the relationship between these architectural features and blood perfusion in silico. If perfusion is defined to be the proportion of vessels that support blood flow, we find that vascular networks with small mean diameters and large numbers of angiogenic sprouts show the largest increases in perfusion post-irradiation for both biological and synthetic tumours. We also identify cases where perfusion increases due to the pruning of hypoperfused vessels, rather than blood being rerouted. These results indicate the importance of considering network composition when determining the optimal irradiation strategy. In the future, we aim to use our findings to identify tumours that are good candidates for perfusion enhancement and to improve the efficacy of combination therapies.

Dependence of cell-free-layer width on rheological parameters: Combining empirical data on flow separation at microvascular bifurcations with geometrical considerations.

When blood flows through vessel networks, red blood cells (RBCs) are typically concentrated close to the vessel center line, creating a lubrication layer near the vessel wall. As RBCs bind oxygen, the width of this cell-free layer (CFL) impacts not only the blood rheology inside the vasculature, but also oxygen delivery to the tissues they perfuse and, hence, their function. Existing attempts to relate the width of the CFL to the rheological properties of the blood and the geometrical properties of the vessel are based on an analysis of the forces acting on RBCs suspended in the blood. However, the complexity of interactions in the blood makes this a challenging task. Here, we propose an alternative, two-step approach to derive such a functional relationship. First, we extend widely accepted empirical fits describing the minimum flow fraction needed for RBCs to enter a daughter vessel downstream of a microvascular bifurcation so that it depends not only on the diameter and discharge haematocrit of the parent vessel, but also on its average shear rate. Second, we propose a simple geometrical model for the minimum flow fraction based on the cross-sectional blood flow profile within the parent vessel upstream of the bifurcation-considering uniform, parabolic, and blunt velocity profiles-and derive the leading-order approximation to this model for small CFL widths. By equating the functional relationships obtained using these two approaches, we derive expressions relating the CFL width to the vessel diameter, discharge haematocrit, and mean shear rate. The resulting expressions are in good agreement with available in vivo data and represent a promising basis for future research.

Abnormal morphology biases hematocrit distribution in tumor vasculature and contributes to heterogeneity in tissue oxygenation.

Oxygen heterogeneity in solid tumors is recognized as a limiting factor for therapeutic efficacy. This heterogeneity arises from the abnormal vascular structure of the tumor, but the precise mechanisms linking abnormal structure and compromised oxygen transport are only partially understood. In this paper, we investigate the role that red blood cell (RBC) transport plays in establishing oxygen heterogeneity in tumor tissue. We focus on heterogeneity driven by network effects, which are challenging to observe experimentally due to the reduced fields of view typically considered. Motivated by our findings of abnormal vascular patterns linked to deviations from current RBC transport theory, we calculated average vessel lengths [Formula: see text] and diameters [Formula: see text] from tumor allografts of three cancer cell lines and observed a substantial reduction in the ratio [Formula: see text] compared to physiological conditions. Mathematical modeling reveals that small values of the ratio λ (i.e., [Formula: see text]) can bias hematocrit distribution in tumor vascular networks and drive heterogeneous oxygenation of tumor tissue. Finally, we show an increase in the value of λ in tumor vascular networks following treatment with the antiangiogenic cancer agent DC101. Based on our findings, we propose λ as an effective way of monitoring the efficacy of antiangiogenic agents and as a proxy measure of perfusion and oxygenation in tumor tissue undergoing antiangiogenic treatment.