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

间充质基质细胞(MSCs)具有良好的免疫调节功能，有望在免疫疾病的治疗中发挥作用。这一承诺目前受到在未分化状态下获得相关数量的MSCs的能力的限制，因此在患者给药之前需要对MSCs进行显著的扩增和生物制造。由于对生物制造对骨髓间充质干细胞行为影响的了解有限，导致骨髓间充质干细胞缺乏成功移植到临床的诸多问题。这组研究人员将通过进行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MSCs的影响，并开发一种新型的3D打印生物材料培养系统，使MSCs能够在受控的微环境中进行可复制的生物制造。该研究项目将与K-12、社区大学和研究生各级的教育和劳动力发展努力相结合。限制MSC临床翻译成功的几个生物制造问题，包括：1)来自不同捐赠者、组织和使用不同条件制造的MSCs之间的异质性；2)缺乏制造MSCs的标准化方法，并且缺乏有效预测特定MSC批次表现的关键质量属性(CQA)；以及3)在生物制造过程中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的研究团队，以1)确定MSC对微环境线索的独特形态响应，预测MSC在大规模3D制造环境中扩张后的功能，以及2)开发使用微孔退火颗粒(MAP)技术的3D打印生物材料培养系统，使MSCs能够扩增具有可复制的免疫调节功能。这些目标的成功将推动未来基于MSC的疗法的制造和翻译，使MSCs能够以可扩展的3D格式进行可复制的扩展，并建立MSC形态作为CQA。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.