肝小叶流量和代谢向全器官规模的双重连续放大

D. Coombe, V. Rezania, J. Tuszynski
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摘要

肝脏是人体的主要代谢器官,其功能在多个时间和空间尺度上运行。在这里,我们使用多尺度建模技术来一致地描述这些函数,基于最初开发的描述自然断裂地质沉积物中反应流体流动过程的方法。使用流量和代谢的完全离散化理想化小叶模型,分两个步骤开发了双连续体方法:1)组织和正弦曲线特性的两个相互作用的连续体模型,然后是2)进一步放大的双连续体模型,得到平均小叶表示。将这两种方法的结果(流量、压力、浓度和反应)与我们的原始模型进行了比较,表明了流量、扩散和反应参数的等效性和近似性。接下来,我们利用一种创新技术,基于已发表的肝脏轮廓和血管系统,利用血管系统生成算法,生成了一个完整肝脏的网格双连续体模型。入口和出口脉管系统根据半径大小分为五代。通过选择1mm3的网格大小,我们得到的离散化模型包含3291430个活动网格单元。在这些细胞中,一部分是占位的脉管系统,而网格细胞的主要剩余部分接近肝小叶。在这里,血管系统的最大世代在横截面和长度上占据多个网格细胞。小叶网格细胞表现为窦状血管系统和组织的双重连续体。这代表了完整肝脏器官的最简单的双重连续网格表示。利用这个基本模型,进行了大量的全肝药物代谢模拟。将仅包括脉管系统和组织之间的对流转移的非反应性PAC(紫杉醇)注射情况与包括额外的扩散转移机制的情况进行比较。然后将这两个病例重新进行组织反应,将注射的PAC转化为PAC-OH(6-羟基紫杉醇)。在没有添加扩散转移的情况下,PAC从脉管系统到组织的转移很少,这对没有反应的情况下的内部PAC分布以及对反应病例的PAC-OH分布都有显著的可观察的影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Dual continuum upscaling of liver lobule flow and metabolism to the full organ scale
The liver is the body’s primary metabolic organ and its functions operate at multiple time and spatial scales. Here we employ multiscale modelling techniques to describe these functions consistently, based on methods originally developed to describe reactive fluid flow processes in naturally-fractured geological sediments. Using a fully discretized idealized lobule model for flow and metabolism, a dual continuum approach is developed in two steps: 1) Two interacting continua models for tissue and sinusoids properties, followed by 2) further upscaled dual continua models leading to an averaged lobule representation. Results (flows, pressures, concentrations, and reactions) from these two approaches are compared with our original model, indicating the equivalences and approximations obtained from this upscaling for flow, diffusion, and reaction parameters. Next, we have generated a gridded dual continuum model of the full liver utilizing an innovative technique, based on published liver outline and vasculature employing a vasculature generation algorithm. The inlet and outlet vasculature systems were grouped into five generations each based on radius size. With a chosen grid size of 1 mm3, our resulting discretized model contains 3,291,430 active grid cells. Of these cells, a fraction is occupied vasculature, while the dominant remaining fraction of grid cells approximates liver lobules. Here the largest generations of vasculature occupy multiple grid cells in cross section and length. The lobule grid cells are represented as a dual continuum of sinusoid vasculature and tissue. This represents the simplest gridded dual continuum representation of the full liver organ. With this basic model, numerous full liver drug metabolism simulations were run. A non-reactive PAC (paclitaxel) injection case including only convective transfer between vasculature and tissue was compared with including an additional diffusive transfer mechanism. These two cases were then rerun with tissue reaction, converting injected PAC to PAC-OH (6-hydroxypaclitaxel). There was little transfer of PAC from vasculature to tissue without the addition of diffusive transfer, and this had a significant observable effect on internal PAC distribution in the absence of reaction, and also on the distribution of PAC-OH for the reactive cases.
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