Numerical Investigations of Hepatic Spheroids Metabolic Reactions in a Perfusion Bioreactor
Numerical Investigations of Hepatic Spheroids Metabolic Reactions in a Perfusion Bioreactor
复制标题
灌注生物反应器中肝球体代谢反应的数值研究
DOI：
--
复制
发表时间：
2019
影响因子：
5.7
通讯作者：
K. Firoozbakhsh
中科院分区：
文献类型：
--
作者：
F. Sharifi;B. Firoozabadi;K. Firoozbakhsh
小型肝细胞培养系统正在成为促进肝脏疾病研究和药物发现的有力工具。然而，对这些系统运行中涉及的各种参数进行实验优化既耗时又昂贵。因此，开发预测此类系统功能的数值工具可以显著降低相关成本。本文研究了一种基于灌注的三维（3D）生物反应器，该反应器由包封的人肝癌（HepG2）球体组成。在三个不同的区域，即自由流动、水凝胶和球形多孔介质部分，求解了氧以及不同代谢物（如白蛋白、葡萄糖、谷氨酰胺、氨和尿素）的流动和传质方程。由于球体被包裹在水凝胶内部，施加在它们身上的剪切应力被发现小于可容忍的阈值。结果表明，7 d培养期间的累积白蛋白浓度与实验数据吻合较好。基于供氧对肝细胞的重要作用，进行了参数化研究，探讨了各参数对肝细胞供氧的影响。结果表明，对流输运机制是主要输运机制，而球内输运机制以扩散输运机制为主。在水凝胶部分，扩散速率和对流机制几乎相同。正如预期的那样，较高的灌注率将为细胞提供高氧水平，并且直径为100 μm的小球体由于扩散氧气穿透深度短，处于低氧状态的风险较低。数值结果表明，在低孔隙度（ε = 0.2 ~ 0.3）条件下，直径为> ~ 200 μm的球体存在缺氧风险，尤其是在靠近岩心的位置。因此，这些结果可能有助于在体外实验中预防缺氧条件。所提出的数值模型提供了一个数值平台，可以帮助研究人员设计和优化复杂的生物反应器，并在任何制造之前的很短时间内获得主要代谢物的数值指标。这些数字指标有助于证明法医调查的结果。
Miniaturized culture systems of hepatic cells are emerging as a strong tool facilitating studies related to liver diseases and drug discovery. However, the experimental optimization of various parameters involved in the operation of these systems is time-consuming and expensive. Hence, developing numerical tools predicting the function of such systems can significantly reduce the associated cost. In this paper, a perfusion-based three dimensional (3D) bioreactor comprising encapsulated human liver hepatocellular carcinoma (HepG2) spheroids are analyzed. The flow and mass transfer equations for oxygen as well as different metabolites such as albumin, glucose, glutamine, ammonia, and urea were solved in three different domains, i.e., free flow, hydrogel, and spheroid porous media sections. Since the spheroids were encapsulated inside the hydrogel, shear stress imposed on them were found to be less than tolerable thresholds. The predicted cumulative albumin concentration over the 7 days of culture period showed a good agreement with the experimental data. Based on the critical role of oxygen supply to the hepatocytes, a parametric study was performed and the effect of various parameters was investigated. Results illustrated that convection mechanism was the dominant transport mechanism in the main-stream section contrary to the intra spheroids parts where the diffusion was the prevailing transport mechanism. In the hydrogel parts, the rate of diffusion and convection mechanisms were almost identical. As expected, higher perfusion rate would provide high oxygen level for the cells and, smaller spheroids with a diameter of 100 μm were at the low risk of hypoxic conditions due to short diffusive oxygen penetration depth. Numerical results evidenced that spheroids with diameter size >200 μm at low porosities (ε = 0.2–0.3) were at risk of oxygen depletion, especially at locations near the core center. Therefore, these results could be beneficial in preventing hypoxic conditions during in vitro experiments. The presented numerical model provides a numerical platform which can help researchers to design and optimize complex bioreactors and obtain numerical indexes of the main metabolites in a very short time prior to any fabrications. Such numerical indexes can be helpful in certifying the outcomes of forensic investigations.
登录
查看更多内容
影响因子：
14
作者：
Yue K;Trujillo-de Santiago G;Alvarez MM;Tamayol A;Annabi N;Khademhosseini A
通讯作者：
Khademhosseini A
DOI：
--
发表时间：
2001-03
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
Li J. Yu;J. Matías;D. Scudiero;K. Hite;A. Monks;E. Sausville;D. Waxman
通讯作者：
Li J. Yu;J. Matías;D. Scudiero;K. Hite;A. Monks;E. Sausville;D. Waxman
影响因子：
2.1
作者：
Soldatow VY;Lecluyse EL;Griffith LG;Rusyn I
通讯作者：
Rusyn I
影响因子：
14
作者：
Skardal, Aleksander;Smith, Leona;Bharadwaj, Shantaram;Atala, Anthony;Soker, Shay;Zhang, Yuanyuan
通讯作者：
Zhang, Yuanyuan
影响因子：
--
作者：
HUTSON, SM;STINSONFISHER, C;JEFFERSON, LS
通讯作者：
JEFFERSON, LS