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Schematic views of the hepatic lobule. Three classic schematics of the liver lobule are; central vein (CV)-centered, portal triads (PT)-centered and acinus. Despite different descriptive views of a liver lobule, the components and functions are the same. PT (blue) consists of hepatic artery, portal vein and bile duct. Blood enters a liver lobule via both hepatic arteries and portal veins, flows across network of liver sinusoids (red), and empties into central vein (CV). During transit, blood-borne substances are absorbed by and metabolized within hepatocytes (green), the major parenchymal cells of the liver, which make up most of liver mass. A liver lobule has three sub-regions (zones) that carry out different metabolic functions. Although definitions for zones vary slightly dependent on the descriptive view, generally, zone I refers to the periportal region; zone II refers to mid-lobular region; zone III refers to pericentral region. Due to both local local microdosimetry and different metabolic functions, the three zones exhibit different types and extents of damage under pathological conditions.
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Computational models of normal liver function and xenobiotic induced liver damage are increasingly being used to interpret in vitro and in vivo data and as an approach to the de novo prediction of the liver’s response to xenobiotics. The microdosimetry (dose at the level of individual cells) of xenobiotics vary spatially within the liver because of...
Citations
... While several 2D/3D models of the liver lobule have been used to investigate the effect of perivenous CYP expression using CYP2E1 as an example, none of the models have systematically investigated the effect of zonation patterns on DILI. Fu et al. studied the effect of periportal, constant, and perivenous zonation patterns on xenobiotic metabolism, but did not study DILI in the form of necrosis [43]. ...
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.
... Given the varied size scales of the liver, Sluka et al. (2016) developed models for these different scales and integrated them into a multiscale model. This model was subsequently expanded upon by Fu et al. (2018), who compared box, pipe and net models to simulate the detoxification of xenobiotics. In addition, Wang et al. (2021) introduced a poro-viscoelastic model, focusing on tumor development within the liver lobules. ...
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.
... Given the varied size scales of the liver, (Sluka et al, 2016) developed models for these different scales and integrated them into a multiscale model. This model was subsequently expanded upon by (Fu et al, 2018), who compared box, pipe and net models to simulate the detoxification of xenobiotics. In addition, (Wang et al, 2021) introduced a poro-viscoelastic model, focusing on tumor development within the liver lobules. ...
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.
... Этот вариант доступа к сосудам для изолированной химиоперфузии печени изучали в режиме однопроходной перфузии у крыс и свиней. Рациональность этого метода основана на данных о том, что опухоли печени преимущественно снабжаются кровью из артериального ложа печени, а печеночные артериолы сливаются с венулами воротной вены в пределах 1-й зоны печеночных синусоид [16,[25][26][27]. Таким образом, реверсирование кровотока через синусоиды из 3-й в 1-ю зону позволяет сохранить действие цитостатика на опухолевую ткань, значительно уменьшив воздействие на паренхиму печени [24,28]. ...
The use of an artificial circulation and endovascular technologies in the treatment of liver metastases of uveal melanoma is a highly relevant area. Uveal melanoma is a rare cancer from the uveal tract of the eye. The liver is the most common site of metastasis and is affected in 70-90% of cases, being the only site of metastasis in about 50% of cases. Survival ranges from two to three months. This literature review describes the following methods of treatment of liver metastases of uveal melanoma using a heart-lung machine: arterial (arterio-caval), portal (porto-caval), arterio-porto-caval, retrograde arterio-portal. Special attention is paid to the endovascular method of treatment.
Literature sources were searched in the following electronic libraries: elibrary.ru, pubmed.ncbi.nlm.nih.gov, researchgate.net.
... Because of its relevance, APAP hepatotoxicity has been modelled by numerous mathematical approaches (Ben-Shachar et al., 2012;Diaz Ochoa et al., 2012;Leclerc et al., 2015;Reddyhoff et al., 2015;Smith et al., 2016;Fu et al., 2018;Franiatte et al., 2019;Sridharan et al., 2021;Heldring et al., 2022). A common computational model approach for drug effects is Physiologically-based (PB) / pharmacokinetic (PK) / pharmacodynamic (PD) models, that mimic either together or separately the concentration changes of the administered drug with time (PK) and its impact on components of interest (cells, tissue, body) (PD), taking often the physiology into account (PB) (Meyer et al., 2012;Upton and Mould, 2014;Kuepfer et al., 2016). ...
In vitro to in vivo extrapolation represents a critical challenge in toxicology. In this paper we explore extrapolation strategies for acetaminophen (APAP) based on mechanistic models, comparing classical (CL) homogeneous compartment pharmacodynamic (PD) models and a spatial-temporal (ST), multiscale digital twin model resolving liver microarchitecture at cellular resolution. The models integrate consensus detoxification reactions in each individual hepatocyte. We study the consequences of the two model types on the extrapolation and show in which cases these models perform better than the classical extrapolation strategy that is based either on the maximal drug concentration (Cmax) or the area under the pharmacokinetic curve (AUC) of the drug blood concentration. We find that an CL-model based on a well-mixed blood compartment is sufficient to correctly predict the in vivo toxicity from in vitro data. However, the ST-model that integrates more experimental information requires a change of at least one parameter to obtain the same prediction, indicating that spatial compartmentalization may indeed be an important factor.
... The Σ 19 PFAS in the 26 wild boar livers ranged between 31.9 and 228 μg/kg, with an average of 87.7 μg/kg, reaching levels significantly higher than in muscles, which exhibited a mean concentration of 3.08 μg/kg (0.59-8.4 μg/kg range) (Table SM5 and Fig. 3). This result was not unexpected considering that liver is a protein-rich organ that is heavily involved in xenobiotic metabolism (Ierapetritou et al., 2009;Fu et al., 2018). Several studies involving various species have demonstrated that it is the target organ for PFASs accumulation and, in mammalian predators, it has been established that PFASs undergo enterophatic recirculation and accumulate primarily in the liver (Kowalczyk et al., 2018;Li et al., 2021;Schrenk et al., 2020). ...
Twenty-six samples of wild boar liver and muscle from the Central Apennine Mountain (Italy) were analysed for 19 perfluoro-alkyl substances (PFASs), 10 polybrominated diphenylethers (PBDEs) and 3 hexabromocyclododecanes (HBCDs). All samples were analysed by gas chromatography–tandem mass spectrometry for PBDEs and liquid chromatography–tandem mass spectrometry for PFASs and HBCDs, using an in-house developed analytical procedure. The brominated flame retardants (BFR) levels in livers were negligible: Σ10PBDEs reached a maximum value of 0.079 μg/kg, whereas HBCDs were not quantified in almost all of the samples analysed. BFR concentrations in muscles were higher, but not significantly therefore, for Σ10PBDEs lower bound, a mean value of 0.045 μg/kg (0.005–0.155 μg/kg range) was measured, while α-HBCD was quantified with a maximum of 0.084 μg/kg in 9 of the samples. Only two muscles contained all 3 HBCD isomers at concentrations of approximately 0.200 μg/kg. Σ19PFAS in the 26 wild boar livers was in the range 31.9–228 μg/kg, with a mean value of 87.7 μg/kg, reaching levels significantly higher than in muscles, which exhibited a mean concentration of 3.08 μg/kg (0.59–9.12 μg/kg range). Perfluorooctanesulfonic acid (PFOS) was the most prevalent compound in all liver samples, accounting for more than half of the total PFASs contamination, confirming that the liver is the primary target organ for PFOS exposure Perfluorotridecanoic acid (PFTrDA), which accounts for 25–30-% of the total contamination, was the most abundant compound in the muscle, followed by PFOS.
The estimated daily intake (EDIs) of BFRs remained below the estimated chronic human daily dietary intake (Dr,h) defined from European Food Safety Authority (EFSA). Furthermore, the exposure to PFASs in muscle was 7.7 times lower than the EFSA's tolerable daily intake (TDI).
In contrast, exposure due to liver consumption was significant: the EDI exceeded the EFSA's 2020 TDI by approximately 7 times.
... 112 Zone I is primarily responsible for ammonia detoxification and glucose metabolism processes. 113 Under reduced perfusion, cells in Zone III are the first to exhibit centrilobular necrosis and accumulate fat. 111 Zonal differences could be seen in liver sinusoidal endothelial cells (LSECs). ...
The liver is the largest internal organ in the human body with largest mass of glandular tissue. Modeling the liver has been challenging due to its variety of major functions, including processing nutrients and vitamins, detoxification, and regulating body metabolism. The intrinsic shortfalls of conventional two-dimensional (2D) cell culture methods for studying pharmacokinetics in parenchymal cells (hepatocytes) have contributed to suboptimal outcomes in clinical trials and drug development. This prompts the development of highly automated, biomimetic liver-on-a-chip (LOC) devices to simulate native liver structure and function, with the aid of recent progress in microfluidics. LOC offers a cost-effective and accurate model for pharmacokinetics, pharmacodynamics, and toxicity studies. This review provides a critical update on recent developments in designing LOCs and fabrication strategies. We highlight biomimetic design approaches for LOCs, including mimicking liver structure and function, and their diverse applications in areas such as drug screening, toxicity assessment, and real-time biosensing. We capture the newest ideas in the field to advance the field of LOCs and address current challenges.
... Liver is an important organ of MPS. Liver consists of two main lobes and more than 1,000 lobules and is connected by hepatic arteries, portal veins, and bile ducts that function as tools for filtration and metabolism of toxic matters and INMs [46][47][48]. The liver possesses an abundant blood supply, playing a crucial role in metabolism, xenobiotic detoxification, glycogen storage, bile formation, protein synthesis [49,50], etc. Liver is mainly composed of parenchymal and nonparenchymal hepatocytes. ...
With excellent physicochemical properties, inorganic nanomaterials (INMs) have exhibited a series of attractive applications in biomedical fields. Biological barriers prevent successful delivery of nanomedicine in living systems that limits the development of nanomedicine especially for sufficient delivery of drugs and effective therapy. Numerous researches have focused on overcoming these biological barriers and homogeneity of organisms to enhance therapeutic efficacy, however, most of these strategies fail to resolve these challenges. In this review, we present the latest progress about how INMs interact with biological barriers and penetrate these barriers. We also summarize that both native structure and components of biological barriers and physicochemical properties of INMs contributed to the penetration capacity. Knowledge about the relationship between INMs structure and penetration capacity will guide the design and application of functional and efficient nanomedicine in the future.
... Because of its relevance, APAP hepatotoxicity has been modelled by numerous mathematical approaches (Ben-Shachar et al., 2012;Diaz Ochoa et al., 2012;Leclerc et al., 2015;Reddyhoff et al., 2015;Smith et al., 2016;Fu et al., 2018;Franiatte et al., 2019;Sridharan et al., 2021;Heldring et al., 2022). A common computational model approach for drug effects is Physiologically-based (PB) / pharmacokinetic (PK) / pharmacodynamic (PD) models, that mimic either together or separately the concentration changes of the administered drug with time (PK) and its impact on components of interest (cells, tissue, body) (PD), taking often the physiology into account (PB) (Meyer et al., 2012;Upton and Mould, 2014;Kuepfer et al., 2016). ...
In vitro to in vivo extrapolation represents a critical challenge in toxicology. In this paper we explore extrapolation strategies for acetaminophen (APAP) based on mechanistic models, comparing classical homogeneous compartment pharmaco-dynamic (PD) models and a multiscale digital twin model resolving liver microarchitecture at cellular resolution. The models integrate consensus detoxification reactions in each individual hepatocyte. We study the consequences of the two model types on the extrapolation and show in which cases these models perform better than the classical extrapolation strategy that is based either on the maximal drug concentration (Cmax) or the area under the pharmaco-kinetic curve (AUC) of the drug blood concentration.
... On top of the large body of in silico models developed for the hepatic circulation and transport, there are proposals to integrate these models into multiscale frameworks, whereby the complex interplay among numerous factors underlying liver function and liver disease may be simulated, and a hypothesis for pathological mechanism may be tested in a virtual setup (D'Alessandro et al., 2015;Fu et al., 2018;Schwen, Schenk, et al., 2015;Sluka et al., 2016). Here we aim to provide an overview of these state-of-the-art in silico models. ...
... In terms of temporal scales, the metabolic time constants are in milliseconds, arterial and sinusoidal flow need to be considered in seconds, and drug clearance from the liver may take hours or even days. Multiscale modeling frameworks have been proposed, for example, in Schliess et al. (2014), Sluka et al. (2016), andFu et al. (2018), where protein-level enzyme kinetics could be coupled to spatial-temporal models of sinusoidal flow, and further to organ or system level of circulation or PBPK models. ...
The function of the liver depends critically on its blood supply. Numerous in silico models have been developed to study various aspects of the hepatic circulation, including not only the macro‐hemodynamics at the organ level, but also the microcirculation at the lobular level. In addition, computational models of blood flow and bile flow have been used to study the transport, metabolism, and clearance of drugs in pharmacokinetic studies. These in silico models aim to provide insights into the liver organ function under both healthy and diseased states, and to assist quantitative analysis for surgical planning and postsurgery treatment. The purpose of this review is to provide an update on state‐of‐the‐art in silico models of the hepatic circulation and transport processes. We introduce the numerical methods and the physiological background of these models. We also discuss multiscale frameworks that have been proposed for the liver, and their linkage with the large context of systems biology, systems pharmacology, and the Physiome project.
This article is categorized under: Metabolic Diseases > Computational Models
Metabolic Diseases > Biomedical Engineering
Cardiovascular Diseases > Computational Models
