Multiple intra-articular injections of umbilical cord mesenchymal stem cells in treating severe knee osteoarthritis: a triple-blind randomized controlled trial

Umbilical cord mesenchymal stem cells (UC-MSCs), with multidirectional differentiation potential, immunomodulatory properties, and paracrine repair functions, have emerged as a promising therapeutic approach for knee osteoarthritis (KOA). This study aimed to compare the 1-year clinical efficacy, structural repair, and safety of multiple intra-articular injections of UC-MSCs versus sodium hyaluronate (SH) in patients with advanced KOA (Kellgren-Lawrence grade III–IV). In this single-center, prospective, triple-blind randomized controlled trial, 50 eligible patients were randomly allocated to the UC-MSCs group ( n = 25) or the SH group ( n = 25). The UC-MSCs group received 4 intra-articular injections at 2-week intervals to sustain continuous paracrine effects and tissue repair, while the SH group received 5 weekly injections following its standard clinical dosing regimen. Evaluations were performed at baseline and 1, 3, 6, and 12 months post-treatment, including the visual analog scale (VAS), Western Ontario and McMaster University Osteoarthritis Index (WOMAC), Lequesne score, subjective satisfaction score, and magnetic resonance imaging (MRI)-based radiological assessments (MOCART cartilage repair score, bone marrow edema remission rate, and meniscal injury repair rate). The UC-MSCs group showed a significantly greater and sustained reduction in VAS scores without rebound: the mean VAS score decreased from 7.2 ± 1.1 to 3.36 ± 0.8 at 12 months (a reduction of 3.84 ± 1.02 points), compared with a decrease from 7.0 ± 1.2 to 4.6 ± 0.9 in the SH group (a reduction of 2.42 ± 0.95 points) ( P < 0.001). The 12-month WOMAC total score decreased by 23.2 ± 6.5 points in the UC-MSCs group (from 62.4 ± 8.7 to 39.2 ± 7.4), which was significantly larger than the 15.6 ± 5.8-point reduction in the SH group (from 60.8 ± 9.2 to 45.2 ± 8.1) ( P < 0.05). For radiological outcomes, the mean MOCART score improved by 13.6 ± 4.2 points in the UC-MSCs group (from 18.2 ± 5.3 to 31.8 ± 6.1), versus 7.8 ± 3.5 points in the SH group (from 17.6 ± 5.1 to 25.4 ± 5.7) ( P < 0.05). The remission rate of femoral bone marrow edema was 80.0% in the UC-MSCs group, significantly higher than 44.0% in the SH group ( P = 0.007). No serious adverse events — defined per CTCAE v5.0 as joint infection, severe allergic reaction, tumorigenesis, or events requiring hospitalization — were observed in either group. Compared with SH, multiple intra-articular injections of UC-MSCs provide more durable pain relief and greater functional improvement in severe KOA, coupled with significant advantages in cartilage repair, bone marrow edema resolution, and meniscal healing. This therapy represents an innovative and effective alternative to traditional conservative management for advanced knee osteoarthritis.