SCILS - Systematic consideration of inhomogeneity at the large scale: towards a stringent development of industrial bioprocesses

该提案涉及英国对已批准的ERA-IB第三跨国项目（在第七个欧盟框架计划的ERA-NET计划内）的贡献，该项目由BG-1生物和地球科学研究所的Marco Oldiges教授领导：生物技术，Forschungszentrum Jülich，FRG。然而，由于生物反应器不均匀性增加的影响，与实验室规模条件相比，全规模生产通常伴随着性能损失。例如，当细胞在大规模生物反应器周围的流动中对流时，它们经历不同的溶解氧（DO）浓度;相比之下，在小规模生物反应器中，更容易确保均匀的DO浓度，因此细胞在整个发酵罐中以相同的方式呼吸和生长。大规模环境中的不均匀性可导致不期望的异质细胞群。应用传统的放大标准来匹配不同规模之间的流体动力学条件是相当困难的;在生产规模下，不均匀性的存在不能简单地通过更强烈的混合来克服，因为所需的能量输入在经济上是不可行的。这些不均匀性问题通常在工程和选择用于生物生产的生物体的合适菌株的早期阶段不被考虑，也不在实验室规模的生物过程开发期间。毫不奇怪，这会导致放大过程中的临界点和故障，需要额外的应变或工艺工程迭代，以实现成功和经济的生产性能。尽管在应变工程和细胞调控过程的理解有很大的进步，考虑的规模效应，如振荡环境的生物系统大多是失踪。缩小这一差距可以在经济效率和低效率之间产生差异，并可以大规模提供更有效的工艺。

The proposal relates to the UK contribution to an approved ERA-IB 3rd Transnational project (within ERA-NET Scheme of the 7th EU Framework Programme) led by Professor Marco Oldiges, Institute of Bio- and Geosciences, IBG-1: Biotechnology, Forschungszentrum Jülich, FRG.Biotechnological production in large scale bioreactors is a state-of-the-art technology. Nevertheless, full scale production is often accompanied by loss of performance compared to lab scale conditions, due to the effects of increasing bioreactor inhomogeneity. For example, cells experience a varying dissolved oxygen (DO) concentration as they are convected in the flow around a large scale bioreactor; in contrast, in small scale bioreactors it is much easier to ensure uniform DO concentrations and hence cells respire and grow in the same way throughout the fermenter. The inhomogeneities in the large scale environment, can lead to heterogeneous populations of cells, which is undesirable. Application of conventional scale-up criteria to match hydrodynamic conditions between different scales is rather difficult; the presence of inhomogeneities cannot simply be overcome at production scales by mixing more intensely, since the required energy inputs are not economically feasible. These inhomogeneity issues are not usually considered at the early stages of engineering and selecting suitable strains of organism for bioproduction, nor during lab-scale bioprocess development. Not surprisingly, this leads to critical points and failures during scale-up, necessitating additional iterations of strain or process engineering to achieve successful and economic production performance. Despite the great advances in strain engineering and understanding of cellular regulatory processes, the consideration of scale up effects such as an oscillatory environment for the biological system is mostly missing. Closing this gap can make the difference between economic efficiency and inefficiency and can provide more efficient processes at large scale.