FMSG: 3D-printed, granular hydrogels for the controlled expansion of mesenchymal stromal cells

FMSG：3D 打印颗粒水凝胶，用于控制间充质基质细胞的扩张

• 批准号: 2036968
• 负责人: Ross Marklein
• 金额: $ 49.93万
• 依托单位: University of Georgia Research Foundation Inc
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2036968&HistoricalAwards=false
• 关键词: FMSG; 3D; printed; granular; hydrogels

Because of their well-established immunomodulatory functions, mesenchymal stromal cells (MSCs) hold promise in the development of therapies for the treatment of immune diseases. This promise is currently limited by the ability to obtain relevant numbers of MSCs in an undifferentiated state, and therefore a significant expansion and biomanufacturing of MSCs is needed prior to patient administration. Multiple issues stemming from the limited understanding of the effects of biomanufacturing on MSC behavior have significantly contributed to the lack of successful translation of MSCs to the clinic. This team of researchers will overcome this limitation by performing basic research to understand the impact of microenvironment during biomanufacturing on MSCs and develop a novel 3D-printed biomaterial culture system that would enable the reproducible biomanufacturing of MSCs in a controlled microenvironment. The research project will be integrated with education and workforce development efforts at all levels from K-12, community college, and graduate levels.Several biomanufacturing issues that have limited the success of MSC clinical translation, including: 1) heterogeneity between MSCs derived from different donors, tissues, and manufactured using different conditions; 2) the lack of standardized approaches to manufacture MSCs and lack of critical quality attributes (CQAs) that effectively predict how a given MSC lot performs; and 3) the unknown impact of changes in 3D microenvironmental cues during biomanufacturing on MSC immunomodulatory function. To address these issues, this project brings together an interdisciplinary research team to 1) identify distinct MSC morphological responses to microenvironment cues that predict MSC function following expansion in a large-scale 3D manufacturing context, and 2) develop a 3D-printed biomaterial culture system using microporous annealed particle (MAP) technology that enables expansion of MSCs with reproducible immunomodulatory function. The success of these aims will advance future manufacturing and the translation of MSC-based therapies by enabling both the reproducible expansion of MSCs in a scalable 3D format and the establishment of MSC morphology as a CQA.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

由于间充质基质细胞（MSC）具有完善的免疫调节功能，因此有望开发出治疗免疫疾病的疗法。目前，这一前景受到获得相关数量的未分化状态间充质干细胞的能力的限制，因此在患者给药之前需要对间充质干细胞进行显着的扩增和生物制造。由于对生物制造对间充质干细胞行为的影响了解有限而产生的多个问题在很大程度上导致了间充质干细胞未能成功转化为临床。 该研究小组将通过开展基础研究来克服这一限制，以了解生物制造过程中微环境对 MSC 的影响，并开发一种新型 3D 打印生物材料培养系统，使 MSC 在受控微环境中实现可重复的生物制造。 该研究项目将与从 K-12、社区大学和研究生各个级别的教育和劳动力发展工作相结合。限制 MSC 临床转化成功的几个生物制造问题，包括：1）来自不同来源的 MSC 之间的异质性供体、组织以及使用不同条件制造的； 2) 缺乏制造 MSC 的标准化方法，并且缺乏有效预测给定 MSC 批次性能的关键质量属性 (CQA)； 3) 生物制造过程中 3D 微环境线索的变化对 MSC 免疫调节功能的未知影响。 为了解决这些问题，该项目汇集了一个跨学科研究团队，以 1) 确定 MSC 对微环境线索的不同形态反应，从而预测 MSC 在大规模 3D 制造环境中扩展后的功能，以及 2) 开发 3D 打印生物材料培养系统使用微孔退火颗粒 (MAP) 技术，能够扩增具有可重复免疫调节功能的 MSC。这些目标的成功将通过以可扩展的 3D 格式实现 MSC 的可重复扩增以及将 MSC 形态建立为 CQA，从而推动未来的制造和基于 MSC 的疗法的转化。该奖项反映了 NSF 的法定使命，并被视为值得通过使用基金会的智力优点和更广泛的影响审查标准进行评估来支持。

项目成果

Shape up before you ship out: morphology as a potential critical quality attribute for cellular therapies

发货前先做好准备：形态学是细胞疗法潜在的关键质量属性

• DOI: 10.1016/j.cobme.2021.100352
• 发表时间: 2021-12
• 期刊: Current Opinion in Biomedical Engineering
• 影响因子: 3.9
• 作者: Daga, Kanupriya R.;Priyadarshani, Priyanka;Larey, Andrew M.;Rui, Kejie;Mortensen, Luke J.;Marklein, Ross A.
• 通讯作者: Marklein, Ross A.