Modeling mass transfer in hepatocyte spheroids via cell viability, spheroid size, and hepatocellular functions
Modeling mass transfer in hepatocyte spheroids via cell viability, spheroid size, and hepatocellular functions
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DOI：
10.1002/bit.20086
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发表时间：
2004-06-20
影响因子：
3.8
通讯作者：
Cohen, S
中科院分区：
文献类型：
--
作者：
Glicklis, R;Merchuk, JC;Cohen, S
肝细胞聚集成球状体有助于其活性增加，但在缺乏血管网络的情况下，大球状体中的细胞经历质量转移限制。因此，需要定义能够实现最大细胞活力和生产力的球状体尺寸。我们开发了一种理论和实验相结合的方法来定义这个最佳球体尺寸。在旋转的T-烧瓶或旋转器中，在孔径为100 μ m的藻酸盐支架中形成肝细胞球状体，以分别产生100、200和600 μ m的最大尺寸。发现细胞活力随着球体尺寸的增加而降低。通过氧质量平衡方程，建立了一个数学模型来描述球体大小与细胞活力之间的关系。这使得能够预测具有不同尺寸的球体中的氧分布曲线和活细胞的分布。该模型描述了没有氧限制将发生在球体直径高达100 μ m。球体大小也影响白蛋白分泌的比速率;它达到最大水平，即，60 μ g/百万细胞/天，在100 μ m直径的球状体中。该行为在将特定白蛋白分泌速率与球体大小相关的方程中描述。计算结果与实验数据吻合，预测需要临界数量的活肝细胞才能获得最大的白蛋白分泌。两者合计，在球状体中的质量传输及其对细胞活力和生产力的影响的结果提供了一个有用的工具，孔径为100 μ m的三维支架的设计。(C)2004 Wiley Periodicals，Inc.
Hepatocyte aggregation into spheroids contributes to their increased activity, but in the absence of a vascular network the cells in large spheroids experience mass transfer limitations, Thus, there is a need to define the spheroid size which enables maximal cell viability and productivity. We developed a combined theoretical and experimental approach to define this optimal spheroid size. Hepatocyte spheroids were formed in alginate scaffolds having a pore diameter of 100 pm, in rotating T-flasks or spinners, to yield a maximal size of 100, 200, and 600 pm, respectively. Cell viability was found to decrease with increasing spheroid size. A mathematical model was constructed to describe the relationship between spheroid size and cell viability via the oxygen mass balance equation. This enabled the prediction of oxygen distribution profiles and distribution of viable cells in spheroids with varying size. The model describes that no oxygen limitation will take place in spheroids up to 100 mum in diameter. Spheroid size affected the specific rate of albumin secretion as well; it reached a maximal level, i.e., 60 mug/million cells/day in 100-mum diameter spheroids. This behavior was depicted in an equation relating the specific albumin secretion rate to spheroid size. The calculated results fitted with the experimental data, predicting the need for a critical number of viable hepatocytes to gain a maximal albumin secretion. Taken together, the results on mass transport in spheroids and its effects on cell viability and productivity provide a useful tool for the design of 3D scaffolds with pore diameters of 100 mum. (C) 2004 Wiley Periodicals, Inc.