Study Design and Participants

This study was an open‐label, single‐arm, single‐center, phase I/II clinical trial with a 24‐week follow‐up period. In addition, we performed long‐term follow‐up to assess safety and efficacy over 7 years. Patients diagnosed with osteoarthritis of the knee joint with Kellgren‐Lawrence (K‐L) grade 3 and painful full‐thickness cartilage defects (International Cartilage Repair Society [ICRS] grade 4 lesions), which were not responsive to more than 6 months of palliative treatment, were eligible to participate. Other inclusion criteria were visual analog scale (VAS) score for pain between 40 and 60 mm during screening; a cartilage defect larger than 2 cm²; swelling, tenderness, and limited range of motion lower than grade 2; adequate blood coagulation activity; and adequate renal and hepatic function. Participants were excluded based on the following criteria: autoimmune or inflammatory joint disease; ligament instability higher than grade 2; a history of infection, surgery, or radiation therapy in the knee joint within the past 6 weeks; enrollment in any other clinical trial within the past 4 weeks; immunosuppressant use within the past 6 weeks; corticosteroid or viscosupplementation injection to the affected knee within the past 3 months; or current pregnancy or lactation.

Two groups were studied to ensure safety of the participants and to determine the maximum tolerated dose (MTD) based on dose‐limiting toxicity (DLT) of the study medicinal product (a composite of allogeneic hUCB‐MSCs and HA hydrogel). The first three participants were assigned to receive low‐dose MSCs (group A), and the next three were assigned to receive high‐dose MSCs (group B) (Table 1). One participant in the low‐dose group did not consent to 12‐week arthroscopy; thus one more participant was assigned to receive low‐dose MSCs (group A) to fulfill the requirement for proceeding to the high‐dose trial. The doses and cell concentrations were selected based on previous animal studies ¹⁵. The allogeneic hUCB‐MSCs were transplanted at a dose of 500 µl/cm² of the defect area with a cell concentration of 0.5 × 10⁷ cells per milliliter. DLT was defined as any case with 2 or more of the following severe adverse reactions after transplantation: swelling, tenderness, limited range of motion, and pain of the knee joint. This study was reviewed and approved by the Korean Food and Drug Administration (FDA) and the institutional review board at our institution (Samsung Medical Center, Seoul, South Korea). Informed consent was obtained from all participants before enrollment in this study.

Baseline and treatment characteristics of study participants