Intra-articular Injection of Mesenchymal Stem Cells After High Tibial Osteotomy in Osteoarthritic Knee: Two-Year Follow-up of Randomized Control Trial

Abstract

Intra-articular injection of adipose-derived mesenchymal stem cell (ADMSC) after medial open-wedge high tibial osteotomy (MOWHTO) would be a promising disease-modifying treatment by correcting biomechanical and biochemical environment for arthritic knee with varus malalignment. However, there is a paucity of clinical evidence of the treatment. This randomized controlled trial (RCT) was aimed to assess regeneration of cartilage defect, functional improvement, and safety of intra-articular injection of ADMSCs after MOWHTO compared with MOWHTO alone for osteoarthritic knee with varus malalignment. This RCT allocated 26 patients into the MOWHTO with ADMSC-injection group (n = 13) and control (MOWHTO-alone) group (n = 13). The primary outcome was the serial changes of cartilage defect on periodic magnetic resonance imaging (MRI) evaluation using valid measurements until postoperative 24 months. Secondary outcomes were the 2-stage arthroscopic evaluation for macroscopic cartilage status and the postoperative functional improvements of patient-reported outcome measures until the latest follow-up. Furthermore, safety profiles after the treatment were evaluated. Cartilage regeneration on serial MRIs showed significantly better in the ADMSC group than in the control group. The arthroscopic assessment revealed that total cartilage regeneration was significantly better in the ADMSC group. Although it was not significant, functional improvements after the treatment showed a tendency to be greater in the ADMSC group than in the control group from 18 months after the treatment. No treatment-related adverse events, serious adverse events, and postoperative complications occurred in all cases. Concomitant intra-articular injection of ADMSCs with MOWHTO had advantages over MOWHTO alone in terms of cartilage regeneration with safety at 2-year follow-up, suggesting potential disease-modifying treatment for knee OA with varus malalignment.

Trial registration: ClinicalTrials.gov NCT03000712.

Keywords: adipose; derived mesenchymal stem cell; high tibial osteotomy; knee; medial open; osteoarthritis; varus malalignment; wedge high tibial osteotomy.

Graphical Abstract

Figure 1.

Consolidated standards of reporting trials (CONSORT) flow diagram (A) and detailed study protocol (B). After screening 29 patients, 26 patients were finally enrolled and randomized to ADMSC group (n = 13) or control group (n = 13). All patients completed a 2-year follow-up; thus full analysis set was performed in this RCT (A). For the ADMSC group, liposuction was conducted 2 weeks before MOWHTO and intraarticular injection of ADMSCs was performed 1 week after MOWHTO under ultrasound guidance. Serial MRI evaluations were performed at postoperative 3, 6, 18, and 24 months and two-stage arthroscopic evaluations of cartilage status were performed at the time of MOWHTO and at the time of plate removal at postoperative 24 months (B). Abbreviations: ADMSC, adipose-derived mesenchymal stem cell; MOWHTO, medial open-wedge high tibial osteotomy; MRI, magnetic resonance imaging; RCT, randomized controlled trial.

Figure 2.

Representative case of MRI and arthroscopic changes after MOWHTO with intra-articular injection of ADMSCs. Preoperative medial compartment OA with varus alignment (A) of the right knee of a 50-year-old female patient is corrected to valgus alignment via MOWHTO (B) and maintained well at postoperative 2 years (C). Preoperative T2-weight sagittal image of MRI shows a full-thickness defect of articular cartilage in the MFC (D). Cartilage regeneration along favorable integration with adjacent native cartilage is observed through serial MRI follow-up up to postoperative 24 months (E-H). Arthroscopic findings of cartilage status in MFC show the exposure of subchondral bone at the time of initial arthroscopy (I) and nearly total coverage of regenerated cartilage 2 years after intra-articular injection of ADMSCs to MOWHTO (J). Abbreviations: ADMSC, adipose-derived mesenchymal stem cell; MFC, medial femoral condyle; MOWHTO, medial open-wedge high tibial osteotomy; MRI, magnetic resonance imaging; OA, osteoarthritis.

Figure 3.

Comparison of mean improvement from baseline in WOMAC scores and KOOS at postoperative 3, 6, 18, and 24 months between intra-articular injection to MOWHTO (ADMSC group) and MOWHTO alone (control group). Patients in the ADMSC group had a tendency to show an improvement in WOMAC stiffness at postoperative 18 (P = .054) and 24 months (P = .054) compared to the control group (A, B). In addition, patients in the ADMSC group had a tendency to show an improvement in WOMAC function (P = .088) and total scores (P = .080) at postoperative 24 months compared to the control group (C, D). Patients in ADMSC group showed significantly higher improvement in KOOS ADL subscale at postoperative 18 (P = .012) and 24 (P = .012) months (E-I). Abbreviations: ADL, activities of daily living; ADMSC, adipose-derived mesenchymal stem cell; KOOS, knee injury and osteoarthritis outcome score; MOWHTO, medial open-wedge high tibial osteotomy; QoL, quality of life; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.