Stem Cell and Cell-Free Strategies for Osteoarthritis: Toward Durable Regenerative Therapies.

Osteoarthritis (OA) is the most prevalent degenerative joint disease and a leading cause of pain and disability, yet current treatments remain largely palliative and fail to alter disease progression. Stem cell-based therapies offer a promising alternative, with mesenchymal stromal/stem cells (MSCs) representing the most clinically advanced approach. Preclinical and clinical studies demonstrate that MSCs exert anti-inflammatory, immunomodulatory, chondroprotective, and analgesic effects primarily through paracrine signaling rather than durable engraftment. Clinical trials consistently confirm intra-articular (IA) MSC safety and symptomatic benefit, though structural outcomes remain variable owing to heterogeneity in cell source, dose, and trial design. This recognition has fueled interest in cell-free derivatives, particularly extracellular vesicles (EVs), which recapitulate MSC paracrine functions while offering improved safety, scalability, and regulatory compatibility. In parallel, bioengineering innovations, including hydrogels, scaffolds, 3D bioprinting, nanotechnology, and genetic enhancement, are being leveraged to prolong persistence, optimize delivery, and enable adaptive, multimodal repair. Emerging sources such as induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), and joint-resident progenitors further expand the regenerative toolkit. These developments suggest that future regenerative strategies for OA may combine cellular therapies, cell-free products, and biomaterial delivery systems to improve treatment durability and therapeutic control.