Ledezma G A, Folch A, Bhatia S N, Balis U J, Yarmush M L, Toner M
Center for Engineering in Medicine, Massachusetts General Hospital, Shriners Burns Hospital, Harvard Medical School, Boston 02114, USA.
J Biomech Eng. 1999 Feb;121(1):58-64. doi: 10.1115/1.2798043.
The incorporation of monolayers of cultured hepatocytes into an extracorporeal perfusion system has become a promising approach for the development of a temporary bioartificial liver (BAL) support system. In this paper we present a numerical investigation of the oxygen tension, shear stress, and pressure drop in a bioreactor for a BAL composed of plasma-perfused chambers containing monolayers of porcine hepatocytes. The chambers consist of microfabricated parallel disks with center-to-edge radial flow. The oxygen uptake rate (OUR), measured in vitro for porcine hepatocytes, was curve-fitted using Michaelis-Menten kinetics for simulation of the oxygen concentration profile. The effect of different parameters that may influence the oxygen transport inside the chambers, such as the plasma flow rate, the chamber height, the initial oxygen tension in the perfused plasma, the OUR, and K(m) was investigated. We found that both the plasma flow rate and the initial oxygen tension may have an important effect upon oxygen transport. Increasing the flow rate and/or the inlet oxygen tension resulted in improved oxygen transport to cells in the radial-flow microchannels, and allowed significantly greater diameter reactor without oxygen limitation to the hepatocytes. In the range investigated in this paper (10 microns < H < 100 microns), and for a constant plasma flow rate, the chamber height, H, had a negligible effect on the oxygen transport to hepatocytes. On the contrary, it strongly affected the mechanical stress on the cells that is also crucial for the successful design of the BAL reactors. A twofold decrease in chamber height from 50 to 25 microns produced approximately a fivefold increase in maximal shear stress at the inlet of the reactor from 2 to 10 dyn/cm2. Further decrease in chamber height resulted in shear stress values that are physiologically unrealistic. Therefore, the channel height needs to be carefully chosen in a BAL design to avoid deleterious hydrodynamic effects on hepatocytes.
将培养的单层肝细胞整合到体外灌注系统中，已成为开发临时生物人工肝（BAL）支持系统的一种很有前景的方法。在本文中，我们对一种用于BAL的生物反应器中的氧张力、剪切应力和压降进行了数值研究，该生物反应器由含有猪肝细胞单层的血浆灌注腔室组成。这些腔室由具有中心到边缘径向流动的微加工平行圆盘组成。使用米氏动力学对体外测量的猪肝细胞氧摄取率（OUR）进行曲线拟合，以模拟氧浓度分布。研究了不同参数对腔室内氧传输的影响，如血浆流速、腔室高度、灌注血浆中的初始氧张力、OUR和米氏常数（K(m)）。我们发现，血浆流速和初始氧张力都可能对氧传输产生重要影响。增加流速和/或入口氧张力可改善径向流微通道中细胞的氧传输，并允许在无肝细胞氧限制的情况下使用直径显著更大的反应器。在本文研究的范围内（10微米 < H < 100微米），对于恒定的血浆流速，腔室高度H对肝细胞的氧传输影响可忽略不计。相反，它对细胞上的机械应力有很大影响，而这对BAL反应器的成功设计也至关重要。腔室高度从50微米降至25微米，会使反应器入口处的最大剪切应力从2达因/平方厘米增加到约10达因/平方厘米，增加近五倍。腔室高度进一步降低会导致剪切应力值不符合生理实际。因此，在BAL设计中需要仔细选择通道高度，以避免对肝细胞产生有害的流体动力学效应。
