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

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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.