Engineering challenges in high density cell culture systems
Engineering challenges in high density cell culture systems
复制标题
DOI：
10.1007/bf00353919
复制
发表时间：
1996-01-01
期刊：
影响因子：
2.2
通讯作者：
Ozturk, SS
中科院分区：
文献类型：
--
作者：
Ozturk, SS
高密度细胞培养系统提供了在紧凑的生物反应器中以高体积生产率生产生物药物的优点;然而，这些系统难以设计和操作。首先，细胞必须在灌注期间通过物理手段保留在生物反应器中。细胞截留率的设计是高密度细胞培养系统性能的关键。氧合和培养基设计对于最大化细胞数量也很重要。在高密度灌注反应器中，可变的细胞密度以及因此的代谢需求需要恒定地调节灌注速率。使用细胞比灌注速率（CSPR）控制为细胞提供恒定的环境，从而导致一致的生产。细胞密度和代谢活性的在线测量可用于细胞密度的估计和CSPR的控制。与传质和混合相关的问题在高细胞密度下变得更加重要。由于氧气和CO2的传质系数不同，使用硅胶管曝气时会出现溶解COP的显著累积。此外，观察到混合在高密度下降低。如果不适当地进行碱添加，则可能导致局部细胞裂解和较差的培养性能。反应器中的不均匀混合促进了培养物的异质性。细胞聚集导致不同混合区内的细胞分离。本文讨论了这些问题，并提出了进一步发展的高密度细胞培养生物反应器的建议。
High density cell culture systems offer the advantage of production of bio-pharmaceuticals in compact bioreactors with high volumetric production rates; however, these systems are difficult to design and operate. First of all, the cells have to be retained in the bioreactor by physical means during perfusion. The design of the cell retention is the key to performance of high density cell culture systems. Oxygenation and media design are also important for maximizing the cell number. In high density perfusion reactors, variable cell density, and hence the metabolic demand, require constant adjustment of perfusion rates. The use of cell specific perfusion rate (CSPR) control provides a constant environment to the cells resulting in consistent production. On-line measurement of cell density and metabolic activities can be used for the estimation of cell densities and the control of CSPR. Issues related to mass transfer and mixing become more important at high cell densities. Due to the difference in mass transfer coefficients for oxygen and CO2, a significant accumulation of dissolved COP is experienced with silicone tubing aeration. Also, mixing is observed to decrease at high densities. Base addition, if not properly done, could result in localized cell lysis and poor culture performance. Non-uniform mixing in reactors promotes the heterogeneity of the culture. Cell aggregation results in segregation of the cells within different mixing zones. This paper discusses these issues and makes recommendations for further development of high density cell culture bioreactors.