基于 "灰箱 "动力学模型的灌注工艺设计新方法

IF 3.5 3区 生物学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Bioprocess and Biosystems Engineering Pub Date : 2024-09-09 DOI:10.1007/s00449-024-03082-5
Chenxi Gao, Weijian Zhang, Liang Zhao, Wen-Song Tan
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引用次数: 0

摘要

灌注细胞培养模式近年来在生物制造领域引起了工业界的兴趣。由于采用了新技术,灌流培养工艺可以支持更高的细胞密度、更高的生产率和更长的工艺时间。然而,由于固有的操作复杂性和高运行成本,灌流培养工艺的开发和设计仍面临挑战。在此,我们介绍一种基于模型的方法,用于设计优化的中国仓鼠卵巢细胞灌流培养。首先,我们使用四批台式反应器连续灌流培养数据来拟合模型参数。然后,我们提出了基于模型的工艺设计方法,旨在快速找出 "理论上最优 "的操作参数组合(灌注速率和灌注培养基中的给料培养基比例),这些参数组合既能达到目标稳态VCD,又能在稳态期间使培养基成本和灌注速率最小化。同时,我们提出了基于模型的动态运行参数调整策略,以解决高浓度灌流介质的高渗透压抑制细胞生长的问题。此外,我们还采用了一种动态反馈控制方法来辅助这一策略,以防止潜在的营养耗竭情况。最后,我们在摇瓶半灌流培养(目标浓度为 5 × 107 cells/ml)和台式反应器连续灌流培养(目标浓度为 1.1 × 108 cells/ml)中测试了基于模型的流程设计方法的可行性。这种方法大大减少了工艺设计和开发所需的实验数量,从而加快了灌流模式细胞培养工艺的发展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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A novel approach for perfusion process design based on a “Grey-Box” kinetic model

Perfusion cell-culture mode has caught industrial interest in the field of biomanufacturing in recent years. Thanks to new technology, perfusion-culture processes can support higher cell densities, higher productivities and longer process times. However, due to the inherent operational complexity and high running costs, the development and design of perfusion-culture processes remain challenging. Here, we present a model-based approach to design optimized perfusion cultures of Chinese Hamster Ovary cells. Initially, four batches of bench-top reactor continuous-perfusion-culture data were used to fit the model parameters. Then, we proposed the model-based process design approach, aiming to quickly find out the “theoretically optimal” operational parameters combinations (perfusion rate and the proportion of feed medium in perfusion medium) which could achieve the target steady-state VCD while minimizing both medium cost and perfusion rate during steady state. Meanwhile, we proposed a model-based dynamic operational parameters-adjustment strategy to address the issue of cell-growth inhibition due to the high osmolality of concentrated perfusion medium. In addition, we employed a dynamic feedback control method to aid this strategy in preventing potential nutrient depletion scenarios. Finally, we test the feasibility of the model-based process design approach in both shake flask semi-perfusion culture (targeted at 5 × 107 cells/ml) and bench-top reactor continuous perfusion culture (targeted at 1.1 × 108 cells/ml). This approach significantly reduces the number of experiments needed for process design and development, thereby accelerating the advancement of perfusion-mode cell-culture processes.

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来源期刊
Bioprocess and Biosystems Engineering
Bioprocess and Biosystems Engineering 工程技术-工程:化工
CiteScore
7.90
自引率
2.60%
发文量
147
审稿时长
2.6 months
期刊介绍: Bioprocess and Biosystems Engineering provides an international peer-reviewed forum to facilitate the discussion between engineering and biological science to find efficient solutions in the development and improvement of bioprocesses. The aim of the journal is to focus more attention on the multidisciplinary approaches for integrative bioprocess design. Of special interest are the rational manipulation of biosystems through metabolic engineering techniques to provide new biocatalysts as well as the model based design of bioprocesses (up-stream processing, bioreactor operation and downstream processing) that will lead to new and sustainable production processes. Contributions are targeted at new approaches for rational and evolutive design of cellular systems by taking into account the environment and constraints of technical production processes, integration of recombinant technology and process design, as well as new hybrid intersections such as bioinformatics and process systems engineering. Manuscripts concerning the design, simulation, experimental validation, control, and economic as well as ecological evaluation of novel processes using biosystems or parts thereof (e.g., enzymes, microorganisms, mammalian cells, plant cells, or tissue), their related products, or technical devices are also encouraged. The Editors will consider papers for publication based on novelty, their impact on biotechnological production and their contribution to the advancement of bioprocess and biosystems engineering science. Submission of papers dealing with routine aspects of bioprocess engineering (e.g., routine application of established methodologies, and description of established equipment) are discouraged.
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