A physiologically-based flow network model for hepatic drug elimination I: regular lattice lobule model

Rezania, Vahid; Marsh, R. E.; Coombe, D.; Tuszyński, Jack A.

doi:10.1186/1742-4682-10-52

Cited by 29 publications

(23 citation statements)

References 32 publications

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“…The flow equations describing reactive-convective-diffusive flow in the liver lobule remain unchanged from our first two papers. Figure 1a and b illustrate the network structure of our base case model discussed in papers I [ 8 ] and II [ 9 ] (which uses a regular sinusoid pattern). Figure 1c represents our model that we study here, which consists of a 2D square lattice clipped by hexagonal boundary with DLA constructed sinusoid network.…”

Section: Methodsmentioning

confidence: 99%

“…In previous papers (papers I [ 8 ] and II [ 9 ]), we proposed a physiologically-based lattice model to study the transport and metabolism of drugs in the liver lobule. In these studies, we constructed a simple regular square lattice model that represents a portion of a liver lobule, see Fig.…”

Section: Introductionmentioning

confidence: 99%

“…The segment represents a typical area studied in our previous papers [ 8 , 9 ]. b Homogeneous lattice (segmented area) with high porosity bands (in red) representing sinusoids and lower porosity regions (in blue) representing tissue containing hepatocytes, as in our previous papers [ 8 , 9 ]. c 2D lobule lattice with sinusoids generated via a diffusion limited aggregation algorithm, this paper.…”

Section: Introductionmentioning

confidence: 99%

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A physiologically-based flow network model for hepatic drug elimination III: 2D/3D DLA lobule models

Rezania

Coombe

Tuszyński

2016

Theor Biol Med Model

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BackgroundOne of the major issues in current pharmaceutical development is potential hepatotoxicity and drug-induced liver damage. This is due to the unique metabolic processes performed in the liver to prevent accumulation of a wide range of chemicals in the blood. Recently, we developed a physiologically-based lattice model to address the transport and metabolism of drugs in the liver lobule (liver functional unit).MethodIn this paper, we extend our idealized model to consider structural and spatial variability in two and three dimensions. We introduce a hexagonal-based model with one input (portal vein) and six outputs (hepatic veins) to represent a typical liver lobule. To capture even more realistic structures, we implement a novel sequential diffusion-limited aggregation (DLA) method to construct a morphological sinusoid network in the lobule. A 3D model constructed with stacks of multiple 2D sinusoid realizations is explored to study the effects of 3D structural variations. The role of liver zonation on drug metabolism in the lobule is also addressed, based on flow-based predicted steady-state O2 profiles used as a zonation indicator.ResultsWith this model, we analyze predicted drug concentration levels observed exiting the lobule with their detailed distribution inside the lobule, and compare with our earlier idealized models. In 2D, due to randomness of the sinusoidal structure, individual hepatic veins respond differently (i.e. at different times) to injected drug. In 3D, however, the variation of response to the injected drug is observed to be less extreme. Also, the production curves show more diffusive behavior in 3D than in 2D.ConclusionAlthough, the individual producing ports respond differently, the average lobule production summed over all hepatic veins is more diffuse. Thus the net effect of all these variations makes the overall response smoother. We also show that, in 3D, the effect of zonation on drug production characteristics appears quite small. Our new biophysical structural analysis of a physiologically-based 3D lobule can therefore form the basis for a quantitative assessment of liver function and performance both in health and diseaseElectronic supplementary materialThe online version of this article (doi:10.1186/s12976-016-0034-5) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A physiologically-based flow network model for hepatic drug elimination III: 2D/3D DLA lobule models

Rezania

Coombe

Tuszyński

2016

Theor Biol Med Model

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“…To summarize many of the concepts outlined in this review, we now present some simple simulations of fluid flow and mechanics at the lobule scale, based on our earlier work [230][231][232]. (A): Figure 1 shows our basic conceptual unit.…”

Section: Basic Concepts Illustrated With Ideal Modelsmentioning

confidence: 99%

“…(B): Next, we constructed an idealized lobule by combining 50 × 50 × 50 units from our basic element, the result of which is shown in Figure 2. Such an approach was first outlined in our earlier papers [230,231], but for 1 /4 element in 2D. Here, there are four inlet (portal) ports and one per-central outlet port, as illustrated in Figure 2.…”

Section: Basic Concepts Illustrated With Ideal Modelsmentioning

confidence: 99%

Liver Bioreactor Design Issues of Fluid Flow and Zonation, Fibrosis, and Mechanics: A Computational Perspective

Rezania

Coombe

Tuszyński

2020

JFB

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Tissue engineering, with the goal of repairing or replacing damaged tissue and organs, has continued to make dramatic science-based advances since its origins in the late 1980’s and early 1990’s. Such advances are always multi-disciplinary in nature, from basic biology and chemistry through physics and mathematics to various engineering and computer fields. This review will focus its attention on two topics critical for tissue engineering liver development: (a) fluid flow, zonation, and drug screening, and (b) biomechanics, tissue stiffness, and fibrosis, all within the context of 3D structures. First, a general overview of various bioreactor designs developed to investigate fluid transport and tissue biomechanics is given. This includes a mention of computational fluid dynamic methods used to optimize and validate these designs. Thereafter, the perspective provided by computer simulations of flow, reactive transport, and biomechanics responses at the scale of the liver lobule and liver tissue is outlined, in addition to how bioreactor-measured properties can be utilized in these models. Here, the fundamental issues of tortuosity and upscaling are highlighted, as well as the role of disease and fibrosis in these issues. Some idealized simulations of the effects of fibrosis on lobule drug transport and mechanics responses are provided to further illustrate these concepts. This review concludes with an outline of some practical applications of tissue engineering advances and how efficient computational upscaling techniques, such as dual continuum modeling, might be used to quantify the transition of bioreactor results to the full liver scale.

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Predicting ADME Properties of Chemicals

Shin¹,

Kang

2017

Handbook of Computational Chemistry

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A physiologically-based flow network model for hepatic drug elimination I: regular lattice lobule model

Cited by 29 publications

References 32 publications

A physiologically-based flow network model for hepatic drug elimination III: 2D/3D DLA lobule models

A physiologically-based flow network model for hepatic drug elimination III: 2D/3D DLA lobule models

Liver Bioreactor Design Issues of Fluid Flow and Zonation, Fibrosis, and Mechanics: A Computational Perspective

Predicting ADME Properties of Chemicals

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