基于动荡参数的细胞和基因疗法生物反应器的扩展策略
Dmytro Iurashev1, Peter Anthony Jones2, Nadejda Andreev2
1Gene Therapy Process Development, Baxalta Innovations GmbH, a part of Takeda companies, Orth an der Donau, Austria.
Biotechnology journal
|October 31, 2023
概括
这项研究引入了Kolmogorov长度参数用于生物反应器扩展,超越输入功率来保护敏感的细胞疗法. 这些发现有助于优化激发和剪切应激,以改善细胞和基因疗法生产.
科学领域:
- 生物技术和生物医学工程 生物技术和生物医学工程
- 细胞和基因疗法制造业 制造业
- 生物工艺工程 生物工艺工程
背景情况:
- 传统的生物反应器扩展依赖于每体积输入功率,假设混合一致.
- 这种方法可以导致敏感细胞的有害切割应激,影响细胞和基因疗法生产.
- 科尔莫戈罗夫长度参数为了解流和剪切分布提供了一个更细致的度量.
研究的目的:
- 研究科尔摩戈罗夫长度参数对生物反应器扩大规模和缩小规模决策的影响.
- 在不同剪切应力条件下评估诱导多能干细胞 (iPSC) 衍生淋巴细胞生产的可扩展性.
- 开发实证模型,以优化细胞和基因疗法制造中的生物反应器操作.
主要方法:
- 使用计算流体动力学 (CFD) 模拟来估计生物反应器中的科尔摩戈罗夫长度分布.
- 模拟涵盖了从0.1L到10L的生物反应器体积,这与流程优化有关.
- 进行了体外实验,以验证计算发现并评估剪切应力影响.
主要成果:
- 该研究估计了Kolmogorov长度沿生物反应器内的粒子轨迹的分布.
- 结果揭示了剪切应力的影响,跨越iPSC衍生的淋巴细胞的不同分化阶段.
- 为了在和生物反应器类型之间进行工艺转移,确定了最佳的动速度和剪切应力调整.
结论:
- 科尔摩戈罗夫长度参数为生物反应器扩大规模提供了关键的见解,超出了传统的输入功率指标.
- 结合实验数据的计算分析支持对细胞和基因疗法的生物反应器和操作条件的明智选择.
- 这种方法提高了敏感的基于细胞的治疗产品的质量和产量.
相关概念视频
Bioreactor Design and Operational System
Bioreactors are engineered vessels designed to cultivate microorganisms under controlled conditions for industrial bioprocessing. They maintain sterility and allow precise regulation of pH, temperature, oxygen, and nutrient levels to optimize microbial growth and metabolite production. Bioreactors range from small laboratory units of 1 liter to industrial systems holding up to 500,000 liters, though only about 75% of their volume is actively used for fermentation. The remaining headspace...
Bioreactor Controls-II
In aerobic fermentations, oxygen is vital for microbial growth and metabolite production. Since air comprises only about 20% oxygen and the gas is poorly soluble in water—just 9 ppm at 20°C—supplying sufficient oxygen becomes a critical challenge, especially in high-demand processes like yeast growth or citric acid production. Even a fully saturated broth may offer only a few seconds of oxygen availability.To address this, sterile or scrubbed air is introduced into the fermentor via a sparger...
Bioreactor Controls-III
Strain improvement is a foundational strategy in industrial microbiology aimed at maximizing microbial productivity, particularly because natural isolates typically yield commercially valuable products in very low concentrations. Although optimizing the culture medium and environmental conditions can improve yields, these adjustments are inherently limited by the organism’s genetic potential. As a result, the focus shifts toward genetic modifications to enhance biosynthetic capacity. The...
Designing Growth Media for Bioreactors
Growth media provide essential nutrients that support cell growth and metabolism, thereby enhancing the yield of valuable products such as enzymes, antibiotics, and biomass. Designing an effective growth medium involves balancing all components to prevent nutrient limitations or toxic excesses, both of which can impair growth and reduce product yields.Composition of a Typical Growth MediumA typical growth medium contains carbon and nitrogen sources, salts, vitamins, trace elements, and...
Scale-Up Processes
The scale-up of microbial fermentation processes is essential in industrial biotechnology, allowing the transition from laboratory-scale experiments to commercial-scale production while aiming to maintain product yield and quality. This process requires meticulous adjustment of equipment design, process parameters, and contamination control strategies to accommodate increasing culture volumes.At the laboratory scale, cultures are typically maintained in 1 to 10-liter glass or autoclavable...
Upstream Processing
Upstream processing represents a critical phase in biomanufacturing, wherein biological systems such as microorganisms, mammalian cells, or insect cells are cultivated to produce therapeutic proteins, vaccines, enzymes, or other biologically derived products. This phase encompasses all steps from the selection and genetic manipulation of the production organism to the cultivation of cells in bioreactors under tightly controlled environmental conditions.Host Selection and Genetic OptimizationThe...


