Bridging Scales: a Hybrid Model to Simulate Vascular Tumor Growth and Treatment Response.

Cancer is a disease driven by random DNA mutations and the interaction of many complex phenomena. To improve the understanding and ultimately find more effective treatments, researchers leverage computer simulations mimicking the tumor growth in silico. The challenge here is to account for the many phenomena influencing the disease progression and treatment protocols. This work introduces a computational model to simulate vascular tumor growth and the response to drug treatments in 3D. It consists of two agent-based models for the tumor cells and the vasculature. Moreover, partial differential equations govern the diffusive dynamics of the nutrients, the vascular endothelial growth factor, and two cancer drugs. The model focuses explicitly on breast cancer cells over-expressing HER2 receptors and a treatment combining standard chemotherapy (Doxorubicin) and monoclonal antibodies with anti-angiogenic properties (Trastuzumab). However, large parts of the model generalize to other scenarios. We show that the model qualitatively captures the effects of the combination therapy by comparing our simulation results with previously published pre-clinical data. Furthermore, we demonstrate the scalability of the model and the associated C++ code by simulating a vascular tumor occupying a volume of 400mm3 using a total of 92.5 million agents.

A phase-field model for non-small cell lung cancer under the effects of immunotherapy.

Formulating mathematical models that estimate tumor growth under therapy is vital for improving patient-specific treatment plans. In this context, we present our recent work on simulating non-small-scale cell lung cancer (NSCLC) in a simple, deterministic setting for two different patients receiving an immunotherapeutic treatment. At its core, our model consists of a Cahn-Hilliard-based phase-field model describing the evolution of proliferative and necrotic tumor cells. These are coupled to a simplified nutrient model that drives the growth of the proliferative cells and their decay into necrotic cells. The applied immunotherapy decreases the proliferative cell concentration. Here, we model the immunotherapeutic agent concentration in the entire lung over time by an ordinary differential equation (ODE). Finally, reaction terms provide a coupling between all these equations. By assuming spherical, symmetric tumor growth and constant nutrient inflow, we simplify this full 3D cancer simulation model to a reduced 1D model. We can then resort to patient data gathered from computed tomography (CT) scans over several years to calibrate our model. Our model covers the case in which the immunotherapy is successful and limits the tumor size, as well as the case predicting a sudden relapse, leading to exponential tumor growth. Finally, we move from the reduced model back to the full 3D cancer simulation in the lung tissue. Thereby, we demonstrate the predictive benefits that a more detailed patient-specific simulation including spatial information as a possible generalization within our framework could yield in the future.

A 1D-0D-3D coupled model for simulating blood flow and transport processes in breast tissue.

In this work, we present mixed dimensional models for simulating blood flow and transport processes in breast tissue and the vascular tree supplying it. These processes are considered, to start from the aortic inlet to the capillaries and tissue of the breast. Large variations in biophysical properties and flow conditions exist in this system necessitating the use of different flow models for different geometries and flow regimes. In total, we consider four different model types. First, a system of 1D nonlinear hyperbolic partial differential equations (PDEs) is considered to simulate blood flow in larger arteries with highly elastic vessel walls. Second, we assign 1D linearized hyperbolic PDEs to model the smaller arteries with stiffer vessel walls. The third model type consists of ODE systems (0D models). It is used to model the arterioles and peripheral circulation. Finally, homogenized 3D porous media models are considered to simulate flow and transport in capillaries and tissue within the breast volume. Sink terms are used to account for the influence of the venous and lymphatic systems. Combining the four model types, we obtain two different 1D-0D-3D coupled models for simulating blood flow and transport processes: The first model results in a fully coupled 1D-0D-3D model covering the complete path from the aorta to the breast combining a generic arterial network with a patient specific breast network and geometry. The second model is a reduced one based on the separation of the generic and patient specific parts. The information from a calibrated fully coupled model is used as inflow condition for the patient specific sub-model allowing a significant computational cost reduction. Several numerical experiments are conducted to calibrate the generic model parameters and to demonstrate realistic flow simulations compared to existing data on blood flow in the human breast and vascular system. Moreover, we use two different breast vasculature and tissue data sets to illustrate the robustness of our reduced sub-model approach.

A 3D-1D coupled blood flow and oxygen transport model to generate microvascular networks.

In this work, we introduce an algorithmic approach to generate microvascular networks starting from larger vessels that can be reconstructed without noticeable segmentation errors. Contrary to larger vessels, the reconstruction of fine-scale components of microvascular networks shows significant segmentation errors, and an accurate mapping is time and cost intense. Thus there is a need for fast and reliable reconstruction algorithms yielding surrogate networks having similar stochastic properties as the original ones. The microvascular networks are constructed in a marching way by adding vessels to the outlets of the vascular tree from the previous step. To optimise the structure of the vascular trees, we use Murray's law to determine the radii of the vessels and bifurcation angles. In each step, we compute the local gradient of the partial pressure of oxygen and adapt the orientation of the new vessels to this gradient. At the same time, we use the partial pressure of oxygen to check whether the considered tissue block is supplied sufficiently with oxygen. Computing the partial pressure of oxygen, we use a 3D-1D coupled model for blood flow and oxygen transport. To decrease the complexity of a fully coupled 3D model, we reduce the blood vessel network to a 1D graph structure and use a bi-directional coupling with the tissue which is described by a 3D homogeneous porous medium. The resulting surrogate networks are analysed with respect to morphological and physiological aspects.

The surrogate matrix methodology: A reference implementation for low-cost assembly in isogeometric analysis.

A reference implementation of a new method in isogeometric analysis (IGA) is presented. It delivers low-cost variable-scale approximations (surrogates) of the matrices which IGA conventionally requires to be computed by element-scale quadrature. To generate surrogate matrices, quadrature must only be performed on a fraction of the elements in the computational domain. In this way, quadrature determines only a subset of the entries in the final matrix. The remaining matrix entries are computed by a simple B-spline interpolation procedure. We present the modifications and extensions required for a reference implementation in the open-source IGA software library GeoPDEs. The exposition is fashioned to help facilitate similar modifications in other contemporary software libraries.•The surrogate matrix methodology is implemented in GeoPDEs.•Poisson's problem is considered.•The matrix assembly time is significantly reduced at negligible cost to solution accuracy.

Cell differentiation defines acute and chronic infection cell types in Staphylococcus aureus.

A central question to biology is how pathogenic bacteria initiate acute or chronic infections. Here we describe a genetic program for cell-fate decision in the opportunistic human pathogen Staphylococcus aureus, which generates the phenotypic bifurcation of the cells into two genetically identical but different cell types during the course of an infection. Whereas one cell type promotes the formation of biofilms that contribute to chronic infections, the second type is planktonic and produces the toxins that contribute to acute bacteremia. We identified a bimodal switch in the agr quorum sensing system that antagonistically regulates the differentiation of these two physiologically distinct cell types. We found that extracellular signals affect the behavior of the agr bimodal switch and modify the size of the specialized subpopulations in specific colonization niches. For instance, magnesium-enriched colonization niches causes magnesium binding to S. aureusteichoic acids and increases bacterial cell wall rigidity. This signal triggers a genetic program that ultimately downregulates the agr bimodal switch. Colonization niches with different magnesium concentrations influence the bimodal system activity, which defines a distinct ratio between these subpopulations; this in turn leads to distinct infection outcomes in vitro and in an in vivo murine infection model. Cell differentiation generates physiological heterogeneity in clonal bacterial infections and helps to determine the distinct infection types.