In silico modeling for the hepatic circulation and transport: From the liver organ to lobules

Ho, Harvey; Means, Shawn; Safaei, Soroush; Hunter, Peter

doi:10.1002/wsbm.1586

Cited by 4 publications

(5 citation statements)

References 138 publications

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“…Aramburu et al (2017). An overview of computational models for blood transport in the liver across scales is provided in Ho et al (2023).…”

Section: State Of the Artmentioning

confidence: 99%

Quantifying Fat Zonation in Liver Lobules: An IntegratedMultiscale In-silico Model Combining DisturbedMicroperfusion and Fat Metabolism via aContinuum-Biomechanical Bi-scale, Tri-phasic Approach

Lambers,

Waschinsky,

Schleicher

et al. 2023

Preprint

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Metabolic zonation refers to the spatial separation of metabolic functions along thesinusoidal axes of the liver. This phenomenon forms the foundation for adjusting hepaticmetabolism to physiological requirements in health and disease (e.g. metabolicdysfunction-associated steatotic liver disease/ MASLD). Zonated metabolic functions areinfluenced by zonal morphological abnormalities in the liver, such as periportal fibrosisand pericentral steatosis. We aim to analyze the interplay between microperfusion,oxygen gradient, fat metabolism and resulting zonated fat accumulation in a liver lobule.Therefore we developed a continuum-biomechanical, tri-phasic, bi-scale, and multicomponent insilicomodel, which allows to numerically simulate coupled perfusion-function-growth interactionstwo-dimensionally in liver lobules. The developed homogenized model has the following specifications:i) thermodynamically consistent, ii) tri-phase model (tissue, fat, blood), iii) penta-substances(glycogen, glucose, lactate, FFA, oxygen), and iv) bi-scale approach (lobule, cell). Our presentedin-silico model accounts for the mutual coupling between spatial and time-dependent liver perfusion,metabolic pathways and fat accumulation. The model thus allows the prediction of fatdevelopment in the liver lobule, depending on perfusion, oxygen and plasma concentration offree fatty acids (FFA), oxidative processes, the synthesis and the secretion of triglycerides (TGs).The use of a bi-scale approach allows in addition to focus on scale bridging processes. Thus,we will investigate how changes at the cellular scale affect perfusion at the lobular scale andvice versa. This allows to predict the zonation of fat distribution (periportal or pericentral)depending on initial conditions, as well as external and internal boundary value conditions.

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“…Aramburu et al (2017). An overview of computational models for blood transport in the liver across scales is provided in Ho et al (2023).…”

Section: State Of the Artmentioning

confidence: 99%

Quantifying Fat Zonation in Liver Lobules: An IntegratedMultiscale In-silico Model Combining DisturbedMicroperfusion and Fat Metabolism via aContinuum-Biomechanical Bi-scale, Tri-phasic Approach

Lambers,

Waschinsky,

Schleicher

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…( 2017 ). An overview of computational models for blood transport in the liver across scales is provided in Ho et al ( 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Quantifying fat zonation in liver lobules: an integrated multiscale in silico model combining disturbed microperfusion and fat metabolism via a continuum biomechanical bi-scale, tri-phasic approach

Lambers,

Waschinsky,

Schleicher

et al. 2024

Biomech Model Mechanobiol

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Metabolic zonation refers to the spatial separation of metabolic functions along the sinusoidal axes of the liver. This phenomenon forms the foundation for adjusting hepatic metabolism to physiological requirements in health and disease (e.g., metabolic dysfunction-associated steatotic liver disease/MASLD). Zonated metabolic functions are influenced by zonal morphological abnormalities in the liver, such as periportal fibrosis and pericentral steatosis. We aim to analyze the interplay between microperfusion, oxygen gradient, fat metabolism and resulting zonated fat accumulation in a liver lobule. Therefore we developed a continuum biomechanical, tri-phasic, bi-scale, and multicomponent in silico model, which allows to numerically simulate coupled perfusion-function-growth interactions two-dimensionally in liver lobules. The developed homogenized model has the following specifications: (i) thermodynamically consistent, (ii) tri-phase model (tissue, fat, blood), (iii) penta-substances (glycogen, glucose, lactate, FFA, and oxygen), and (iv) bi-scale approach (lobule, cell). Our presented in silico model accounts for the mutual coupling between spatial and time-dependent liver perfusion, metabolic pathways and fat accumulation. The model thus allows the prediction of fat development in the liver lobule, depending on perfusion, oxygen and plasma concentration of free fatty acids (FFA), oxidative processes, the synthesis and the secretion of triglycerides (TGs). The use of a bi-scale approach allows in addition to focus on scale bridging processes. Thus, we will investigate how changes at the cellular scale affect perfusion at the lobular scale and vice versa. This allows to predict the zonation of fat distribution (periportal or pericentral) depending on initial conditions, as well as external and internal boundary value conditions.

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“…The perfusion in liver lobules can therefore be modeled in sinusoids in healthy livers [16, 17] or in fibrotic and cirrhotic livers [18]. An overview for cellular scales is given in [19], for lobular scales in [19, 20, 21].…”

Section: Introductionmentioning

confidence: 99%

Simulation of zonation-function relationships in the liver using coupled multiscale models: Application to drug-induced liver injury

Gerhäusser,

Lambers,

Mandl

et al. 2024

Preprint

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Multiscale modeling requires the coupling of models on different scales, often based on different mathematical approaches and developed by different research teams. This poses many challenges, such as defining interfaces for coupling, reproducible exchange of submodels, efficient simulation of the models, or reproducibility of results. Here, we present a multiscale digital twin of the liver that couples a partial differential equation (PDE)-based porous media approach for the hepatic lobule with cellular-scale ordinary differential equation (ODE)-based models. The models based on the theory of porous media describe transport, tissue mechanical properties, and deformations at the lobular scale, while the cellular models describe hepatic metabolism in terms of drug metabolism and damage in terms of necrosis. The resulting multiscale model of the liver was used to simulate perfusion-zonation-function relationships in the liver spanning scales from single cell to the lobulus. The model was applied to study the effects of (i) protein zonation patterns (metabolic zonation) and (ii) drug concentration dependence on spatially heterogeneous liver damage in the form of necrosis. Depending on the zonation pattern, different liver damage patterns could be reproduced, including periportal and pericentral necrosis as seen in drug-induced liver injury (DILI). Increasing the drug concentration led to an increase in the observed damage pattern. A key point for the success was the integration of domain-specific simulators based on standard exchange formats, i.e., libroadrunner for the high-performance simulation of ODE-based systems and FEBio for the simulation of the continuum-biomechanical part. This allows a standardized and reproducible exchange of cellular scale models in the Systems Biology Markup Language (SBML) between research groups.

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In silico modeling for the hepatic circulation and transport: From the liver organ to lobules

Cited by 4 publications

References 138 publications

Quantifying Fat Zonation in Liver Lobules: An IntegratedMultiscale In-silico Model Combining DisturbedMicroperfusion and Fat Metabolism via aContinuum-Biomechanical Bi-scale, Tri-phasic Approach

Quantifying Fat Zonation in Liver Lobules: An IntegratedMultiscale In-silico Model Combining DisturbedMicroperfusion and Fat Metabolism via aContinuum-Biomechanical Bi-scale, Tri-phasic Approach

Quantifying fat zonation in liver lobules: an integrated multiscale in silico model combining disturbed microperfusion and fat metabolism via a continuum biomechanical bi-scale, tri-phasic approach

Simulation of zonation-function relationships in the liver using coupled multiscale models: Application to drug-induced liver injury

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