Next-generation therapies for osteoarthritis: the evolving role of cell therapy products

www.nature.com/emm REVIEW ARTICLE OPEN Next-generation therapies for osteoarthritis: the evolving role of cell therapy products ✉ Valtteri Peitso 1 , Ron Ellis 2, Karman Ng Nancy P. Duarte-Delgado 1, Tobias Winkler ✉ Ali Mobasheri 1,13,14,15,16,17 2 , Simone Ponta 3, Rana Smaida 4,5,6, Nadia Benkirane-Jessel , Goncalo Barreto 11, Jean-Yves Reginster 12 and 4,5,6 , 7,8,9,10 1234567890();,: © The Author(s) 2026 Osteoarthritis (OA) remains a major cause of disability worldwide; however, current non-surgical treatments offer transient symptom relief without altering disease course. This leaves a therapeutic gap for patients with early-to-moderate disease who are not candidates for surgery but continue to experience pain and functional limitation. Intra-articular interventions such as nonsteroidal anti-inflammatory drugs, hyaluronic acid, and platelet-rich plasma may ease symptoms, but do not modify disease progression. By contrast, cell therapy products hold promise as regenerative approaches that may both alleviate pain and influence disease trajectory. Cell therapy products for knee OA exert multimodal effects through paracrine and immunomodulatory mechanisms, including modulation of synovial inflammation, attenuation of senescence-associated pathways, and support of extracellular matrix production. Despite encouraging preclinical and clinical signals, only a few cell therapy products have been approved globally, and most remain in development. However, substantial translational challenges remain, including variability in cell source and potency, limited persistence in joint environment, small clinical trial sizes, and regulatory and manufacturing hurdles. To achieve broader adoption, it will be essential to demonstrate superiority to minimally manipulated orthobiologics, clarify redosing strategies, and generate robust long-term evidence. This Review discusses recent clinical trial data, mechanistic insights, regulatory considerations, and operational challenges shaping the evolving role of cell therapy products for OA as nextgeneration candidates to bridge the gap between pharmacological and surgical interventions. In addition, this Review is written to support regulatory agencies as well as academics and clinicians involved in the development and evaluation of cell therapy products. Experimental & Molecular Medicine; https://doi.org/10.1038/s12276-026-01726-y INTRODUCTION Osteoarthritis (OA) affects more than 600 million adults globally and is among the leading causes of disability worldwide1,2. As the prevalence of OA continues to rise owing to aging and obesity, the burden on health-care systems grows correspondingly. Current OA treatment paradigms rely heavily on non-orthobiological symptommodifying agents including non-steroidal anti-inflammatory drugs, corticosteroids (CS), and hyaluronic acid (HA), as well as orthobiologics, referred here as minimally manipulated autologous products, such as platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC)3–6 (Fig. 1). Although these approaches may provide transient relief based on patient characteristics and severity of OA, they do not modify the underlying disease progression4,6,7. In fact, repeated CS injections are associated with an increased risk of chondrotoxicity6. As a result, patients often experience years of inadequate pain control and functional limitation before progressing to surgical eligibility. Although total knee arthroplasty (TKA) is an effective intervention for end-stage OA, the treatment gap for patients with moderate disease remains unaddressed8,9. These patients are often symptomatic yet are not suitable candidates for surgical intervention and have few-to-no durable therapeutic options, highlighting the critical need for effective therapies after the aforementioned ones have failed; or if disease-modifying, the potential to treat patients earlier in the OA course (Fig. 1). Cell-based 1 Research Unit of Health Sciences and Technology, Faculty of Medicine, University of Oulu, Oulu, Finland. 2Independent Researcher, Tampa, FL, USA. 3Tissue Engineering + Biofabrication Laboratory, Department of Health Sciences and Technology, ETH Zürich, Zürich, Switzerland. 4Lamina Therapeutics, Strasbourg, France. 5Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1260, Regenerative NanoMedicine (RNM), Strasbourg, France. 6Université de Strasbourg, Strasbourg, France. 7Center for Musculoskeletal Surgery, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charité — Universitätsmedizin Berlin, Berlin, Germany. 8Julius Wolff Institute, Berlin Institute of Health, Charité — Universitätsmedizin Berlin, Berlin, Germany. 9Berlin Institute of Health Center for Regenerative Therapies, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin and Berlin Institute of Health, Charité — Universitätsmedizin Berlin, Berlin, Germany. 10Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Vienna, Austria. 11Clinicum, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 12Protein Research Chair, Department of Biochemistry, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia. 13Department of Personalized Medicine, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania. 14Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. 15Faculty of Medicine, Université de Liège, Liège, Belgium. 16Department for Health Sciences, Medicine and Research, Center for Regenerative Medicine, Faculty of Health and Medicine, University for Continuing Education Krems, Krems, Austria. 17Department of Orthopedic Surgery, Maastricht University Medical Center, Maastricht University, Maastricht, Netherlands. ✉email: valtteri.peitso@oulu.fi; ali.mobasheri@oulu.fi Received: 12 January 2026 Accepted: 8 March 2026 V. Peitso et al. 2 Fig. 1 Current osteoarthritis treatment paradigm. Current osteoarthritis (OA) treatment paradigm consists of: (1) non-steroidal antiinflammatory drugs administered orally or topically during the early stages of OA; (2) non-orthobiological intra-articular injections such as corticosteroids (CSs) or hyaluronic acid (HA), and orthobiological injections including platelet-rich plasma (PRP) or bone marrow aspirate concentrate (BMAC), also primarily used in early stages of OA; (3) prospective cell therapy products, mainly delivered through intra-articular injection, intended to bridge the therapeutic gap between early-stage and late-stage OA; (4) total knee arthroplasty as the final intervention when disease progression continues despite the aforementioned treatments. Figure created with BioRender. Box 1. Regulatory expectations for cell therapy products European and American regulatory expectations increasingly focus on12,13,157–159: • Cell viability assays • Correlation between viable cell (...truncated)