Alan T.L. Lam, Shaul Reuveny and Steve Kah-Weng Oh
Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore
Published in Stem Cell Research 2020 44: 101738 (Online Version)
Articular cartilage defects are a major challenge in orthopedic and trauma surgery due to the poor ability of cartilage to self-repair. Mesenchymal stem cells (MSC), which can grow extensively and can form functional cartilage, have emerged as a promising therapy for cartilage defects. Currently, clinicians can treat cartilage defects by mixing MSC or MSC-derived chondrocytes with a sealant or sometimes a biodegradable scaffold and injecting the mixture into the defect.
However, MSC-based cartilage therapy still faces multiple challenges. In this review, we provide an overview of the major challenges including MSC isolation from different sources, characterization, large-scale manufacturing, in vitro differentiation, and procedures related to sealant-based or scaffold-based implantation (see below schematic diagram). We then review the many preclinical and clinical studies directed towards MSC based cartilage therapy. Using MSCs or MSC-derived chondrocytes from a variety of sources embedded in different sealants and sometimes attached to a solid scaffold demonstrated different levels of success, indicating room for optimization. Finally, we discuss how the key remaining challenges can be addressed.
In order to establish a reproducible GMP-qualified production process, more standards for quality control are needed to assess the quality, efficacy, and safety of MSC during their production for the final clinical use. This may include genomic stability test, contamination assessment, cytokine release assay and more. Development of efficient serum-free and xeno-free media for cell isolation, propagation, and even differentiation have to be addressed. Downstream processing such as cell harvesting and removal of microcarriers and particulates from the cell products still need to be further explored. Lastly for achieving high doses for therapy, it is also crucial to implement efficient initial cell isolation, GMP-qualified large-scale expansion of this cell population towards clinically relevant cell numbers and the final construct development into one integrated bioprocess with automation.
This work was led by Dr. Steve Oh at BTI, who is Co-PI with Dr. Simon Cool of the Allogenic Stem Cell Manufacturing (ASTEM) program, funded by the Industry Alignment Fund Pre-Positioning (IAF-PP) grant from the Health and Biomedical Sciences (HBMS), Singapore.
Figure 1. A simple scheme of MSC isolation, characterization, current manufacturing platforms using various bioreactors, in vitro differentiation, and sealant-based or scaffold-based implantation for cartilage defects repair.