Herbst Laura, Nießing Bastian, Schmitt Robert H
Department Bio-Adaptive production, Fraunhofer Institute for Production Technology (FHG), Aachen, Germany.
WZL RWTH Aachen, Chair of Intelligence in Quality Sensing, Laboratory for Machine Tools and Production Engineering, RWTH Aachen University, Aachen, Germany.
Front Bioeng Biotechnol. 2025 Aug 21;13:1608194. doi: 10.3389/fbioe.2025.1608194. eCollection 2025.
Mesenchymal stem/stromal cells (MSCs) have been identified as a promising therapeutic option for osteoarthritis, graft vs. host disease and cardiovascular diseases, among others. For widespread application of these therapies, robust and scaled manufacturing processes are required that reliably yield high amounts of high quality MSCs. One of the primary challenges in MSC manufacturing is achieving robustness, due to the high donor-to-donor and batch-to-batch variability seen in MSC manufacturing. To achieve more consistent manufacturing, standardization of the manufacturing process and analytical methods to determine cell quality and control process parameters will be needed. Traditionally, MSCs are cultivated in two dimensional (2D) systems, such as flasks or plates. However, these systems are limited in their scalability. To enhance volumetric productivity, upscaling may be achieved using agitated bioreactors where the MSCs are grown on microcarriers or other types of scaffolds. In this article, we have reviewed existing publications on the manufacturing of MSCs in agitated bioreactor systems regarding the process conditions used and the quality parameters measured to define more clearly the most relevant cell quality and process parameters. Key cell quality parameters measured are cell number and viability, immunophenotype and differentiation potential, while key process parameters include the cultivation system (cell source, bioreactor type, media composition), physiochemical properties of the media such as pH and dissolved oxygen (DO), as well as nutrient supply. Defining these parameters more clearly will support the development of robust MSC manufacturing processes at scale using improved process control and facilitate the widespread clinical application of MSC-based cell therapies.
间充质干/基质细胞（MSCs）已被确定为骨关节炎、移植物抗宿主病和心血管疾病等疾病的一种有前景的治疗选择。为了这些疗法的广泛应用，需要强大且可扩展的制造工艺，以可靠地生产大量高质量的MSCs。由于在MSCs制造过程中观察到供体间和批次间的高度变异性，MSCs制造的主要挑战之一是实现稳健性。为了实现更一致的制造，将需要制造工艺和分析方法的标准化，以确定细胞质量和控制工艺参数。传统上，MSCs在二维（2D）系统中培养，如培养瓶或培养板。然而，这些系统的可扩展性有限。为了提高体积生产率，可以使用搅拌生物反应器进行放大，其中MSCs生长在微载体或其他类型的支架上。在本文中，我们回顾了关于在搅拌生物反应器系统中制造MSCs的现有出版物，涉及所使用的工艺条件和测量的质量参数，以更清楚地定义最相关的细胞质量和工艺参数。测量的关键细胞质量参数是细胞数量和活力、免疫表型和分化潜能，而关键工艺参数包括培养系统（细胞来源、生物反应器类型、培养基组成）、培养基的物理化学性质，如pH值和溶解氧（DO），以及营养供应。更清楚地定义这些参数将支持使用改进的过程控制大规模开发稳健的MSCs制造工艺，并促进基于MSCs的细胞疗法的广泛临床应用。
