Clinical Trials with Mesenchymal Stem Cell Therapies for Osteoarthritis: Challenges in the Regeneration of Articular Cartilage

Abstract

Osteoarthritis (OA) is a whole-joint disease primarily characterized by the deterioration of hyaline cartilage. Current treatments include microfracture and chondrocyte implantation as early surgical strategies that can be combined with scaffolds to repair osteochondral lesions; however, intra-articular (IA) injections or implantations of mesenchymal stem cells (MSCs) are new approaches that have presented encouraging therapeutic results in animal models and humans. We critically reviewed clinical trials with MSC therapies for OA, focusing on their effectiveness, quality, and outcomes in the regeneration of articular cartilage. Several sources of autologous or allogeneic MSCs were used in the clinical trials. Minor adverse events were generally reported, indicating that IA applications of MSCs are potentially safe. The evaluation of articular cartilage regeneration in human clinical trials is challenging, particularly in the inflammatory environment of osteoarthritic joints. Our findings indicate that IA injections of MSCs are efficacious in the treatment of OA and the regeneration of cartilage, but that they may be insufficient for the full repair of articular cartilage defects. The possible interference of clinical and quality variables in the outcomes suggests that robust clinical trials are still necessary for generating reliable evidence with which to support these treatments. We suggest that the administration of just-sufficient doses of viable cells in appropriate regimens is critical to achieve effective and durable effects. In terms of future perspectives, genetic modification, complex products with extracellular vesicles derived from MSCs, cell encapsulation in hydrogels, and 3D bioprinted tissue engineering are promising approaches with which to improve MSC therapies for OA.

Keywords: cartilage regeneration; clinical trials; intra-articular injection; mesenchymal stem cells; osteoarthritis.

Figure 1

Mesenchymal stem cell therapy strategies in the treatment of OA. (a) Intra-articular injection of MSCs: autologous or allogeneic culture-expanded MSCs are harvested and injected into the articular cavity, where they produce immunomodulatory factors, trophic factors, and extracellular vesicles that induce cartilage defect regeneration and the alleviation of symptoms. (b) Autologous mesenchymal stem cell implantation (AMI): autologous culture-expanded MSCs are implanted back into cartilage defects with fibrin glue. (c) Matrix-assisted autologous mesenchymal stem cell implantation (MAMI): a bioscaffold is applied to the cartilage defect with culture-expanded MSCs.

Figure 2

Main clinical variables of the clinical trials (total = 35). (a) Number of studies for each tissue source of MSCs. (b) Number of studies with short-, mid-, and long-term follow-ups. (c) Number of studies with small, average, and large numbers of participants. (d) Number of studies presenting participants diagnosed with mild (I–III) or severe (IV) OA grades.

Figure 3

Assessment of the main outcomes described in the clinical trials. (a) Number of studies for each fold improvement of outcome scores. (b) Number of studies with or without significant MRI improvement. (c) Number of studies with minimum clinically important WOMAC score changes (≥17). (d) WOMAC score changes presented by IA-injected MSC doses from 15 studies.