A Narrative Review on Manufacturing Methods Employed in the Production of Mesenchymal Stromal Cells for Knee Osteoarthritis Therapy

Abstract

Knee osteoarthritis (OA) is a chronic, progressive, inflammatory, and degenerative whole-joint disease. Early-stage OA treatments typically include physiotherapy, weight-loss, pain relief medications, and intra-articular knee injections, such as corticosteroids, hyaluronic acid, or platelet-rich plasma. These treatments primarily provide symptomatic relief rather than reversing or halting disease progression. Recently, mesenchymal stromal cell (MSC) injections have garnered attention due to their immunomodulatory and regenerative capacities. MSCs, which can be derived from sources such as bone marrow, umbilical cord, or adipose tissue, and can be allogeneic or autologous, have demonstrated promising results in both animal models and several human studies. However, different protocols have been employed, presenting challenges for comparing outcomes. In this review, we address these variable settings, evaluate current practices, and identify key factors critical in optimizing MSC-based therapies by critically reviewing clinical trials of ex vivo expanded MSC therapies for OA undertaken between 2008 and 2023. Specific attention was given to two key aspects: (1) the cell culture process employed in manufacturing of autologous or allogeneic MSC products, and (2) the post-culture methods employed in storage, reconstitution and administration of the MSCs. Our findings suggest that standardizing MSC production for clinical applications remains a significant challenge, primarily due to variations in tissue sources, harvesting techniques, and manufacturing protocols, and due to broad discrepancies in reporting. Thus, we propose a set of minimal reporting criteria to guide future clinical trials. A common reporting guideline is a critical step towards a more standardized MSC production across different laboratories and clinical settings, thereby enhancing reproducibility and advancing the field of regenerative medicine for knee OA, as well as other disease settings.

Keywords: advanced therapy medicinal product; cell culture; cell storage; cryopreservation; knee osteoarthritis; mesenchymal stromal cells; reconstitution; thawing; viability.

Figure 1

Schematic overview of the MSC manufacturing process. Step-by-step production of MSCs from tissue procurement and isolation from various tissue sources to expansion and cell harvesting. Production is illustrated for both fresh and cryopreserved MSCs (green bar showing the process for MSC therapy with fresh cells, blue bar showing it for cryopreserved cells). (MSC = Mesenchymal stromal cell). Biorender was used to create Figure 1.