Clinical Review

Intra-Articular Injections of Mesenchymal Stem Cells for Knee Osteoarthritis

Am J Orthop. 2014 December;43(12):E282-E291

Knee osteoarthritis (KOA) represents an enormous societal burden. This review article summarizes the knowledge on the efficacy of using intra-articular injections of mesenchymal stem cells (MSCs) to treat KOA.

PubMed (Medline) and the Cochrane Library were searched for literature related to MSC therapy and KOA up until January 31, 2014. The key search terms used were stem cells and knee osteoarthritis. One hundred thirty-five reports were found, but only the 25 fully focused on the topic were used for analysis.

Only 3 randomized controlled trials (level II evidence) found pain relief and functional improvement over the short term. The other human studies also reported encouraging results, but their evidence level was very low (IV).

Larger randomized controlled trials are needed to support these preliminary encouraging results. The relatively short duration of the studies is also a limitation for the technique at present.

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References

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2. Filardo G, Madry H, Jelic M, Roffi A, Cucchiarini M, Kon E. Mesenchymal stem cells for the treatment of cartilage lesions: from preclinical findings to clinical application in orthopaedics. Knee Surg Sports Traumatol Arthrosc. 2013;21(8):1717-1729.

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9. Suhaeb AM, Naveen S, Mansor A, Kamarul T. Hyaluronic acid with or without bone marrow derived-mesenchymal stem cells improves osteoarthritic knee changes in rat model: a preliminary report. Indian J Exp Biol. 2012;50(6):383-390.

10. Al Faqeh H, Nor Hamdan BM, Chen HC, Aminuddin BS, Ruszymah BH. The potential of intra-articular injection of chondrogenic-induced bone marrow stem cells to retard the progression of osteoarthritis in a sheep model. Exp Gerontol. 2012;47(6):458-464.

11. Toghraie F, Razmkhah M, Gholipour MA, et al. Scaffold-free adipose-derived stem cells (ASCs) improve experimentally induced osteoarthritis in rabbits. Arch Iran Med. 2012;15(8):495-499.

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Knee osteoarthritis (KOA), a common disabling disease with a high impact on quality of life, has a large societal cost. Yet no procedure halts progressive degeneration of the osteoarthritic knee joint.^1,2

According to Barry,³ mesenchymal stem cells (MSCs) differentiate into many different connective tissue cells, including cartilage. MSCs can be isolated from bone marrow, skeletal muscle, fat, and synovium. MSCs are multipotent cells with the capacity for self-renewal. Therefore, adult MSCs may regenerate tissues damaged by disease. In OA, the proliferative capacity and ability to differentiate are reduced in MSCs. Intra-articular injections of MSCs (MSC therapy) could repair progressively degenerated knee cartilage.

This review article summarizes the knowledge on the role of intra-articular injections of MSCs in the treatment of KOA, based on studies published in PubMed and the Cochrane Library. The article also reviews the methodology and results of the animal and clinical studies published so far on the topic.

Materials and Methods

PubMed (Medline) and the Cochrane Library were searched for literature on the role of MSC therapy in treating KOA. The key words used were stem cells and knee osteoarthritis. The period searched was from when these search engines began until January 31, 2014. One hundred thirty-five articles (including negative studies) were found, but only the 25 deeply focused on the topic were reviewed. The Figure shows the flow diagram of this study.

Results

Several experimental models of KOA have shown that MSC therapy can delay progressive degeneration of the knee joint (Appendix 1).^4-15 Using a rabbit massive meniscal defect model, Hatsushika and colleagues¹³ found that a single intra-articular injection of synovial MSCs into the knee adhered around the meniscal defect and promoted meniscal regeneration. Park and colleagues¹⁴ conducted an experimental study in dogs—the first demonstrating regional and systemic safety and systemic immunomodulatory effects of repeated local delivery of allogeneic MSCs in vivo. Regarding the observed systemic immunomodulatory effects, clinical and pathologic examinations revealed no severe consequences of repeated MSC transplantations. Results of mixed leukocyte reactions demonstrated suppression of T-cell proliferation after MSC transplantations.

Of the human studies published so far, only 3 were prospective randomized trials (level II evidence) included in the Cochrane Library (Appendix 2).^16-18 Varma and colleagues¹⁶found that intra-articular injections of MSCs considerably improved overall KOA outcome scores. Fifty patients with mild to moderate KOA were divided into 2 groups. Group A underwent arthroscopic débridement, and group B had buffy coat (MSC concentrate) injection and arthroscopic débridement. Patients were assessed on the basis of their visual analog scale (VAS) pain scores and osteoarthritis outcome scores.

Wong and colleagues¹⁷ analyzed 56 knees in 56 patients (mean age, 51 years) with unicompartmental KOA and genu varum. Patients were randomly assigned to 2 groups, MSC and control. All patients underwent high tibial osteotomy (HTO) and microfracture. Patients in the MSC group received intra-articular injection of cultured MSCs with hyaluronic acid (HA) 3 weeks after surgery. Patients in the control group received only HA. The primary outcome measure was International Knee Documentation Committee (IKDC) score 6 months, 1 year, and 2 years after surgery. Secondary outcome measures were Tegner and Lysholm clinical scores and 1-year postoperative Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scores. Both treatment arms achieved improvements in Tegner, Lysholm, and IKDC scores. After adjustment for age, baseline scores, and time of evaluation, the MSC group had significantly better scores. One year after surgery, magnetic resonance imaging (MRI) scans showed significantly better MOCART scores for the MSC group. Intra-articular injection of MSCs appeared to be effective in improving short-term clinical and MOCART outcomes in patients who underwent HTO and microfracture for varus knees with cartilage defects.

Saw and colleagues¹⁸ compared histologic and MRI evaluation of articular cartilage regeneration in patients with chondral lesions treated by arthroscopic subchondral drilling followed by postoperative intra-articular injections of HA with and without peripheral blood stem cells (PBSCs). Fifty patients (ages, 18-50 years) with International Cartilage Repair Society grades 3 and 4 lesions of the knee joint underwent arthroscopic subchondral drilling; 25 patients were randomized to the intervention group (HA + PBSC) and 25 to the control group (HA). Both groups received 5 weekly injections starting 1 week after surgery. Three additional injections of either HA + PBSC or HA only were given at weekly intervals 6 months after surgery. After arthroscopic subchondral drilling into grades 3 and 4 chondral lesions, postoperative intra-articular injections of autologous PBSC combined with HA resulted in improved quality of articular cartilage repair over the same treatment without PBSC.

The other human studies analyzed had a low level of evidence (grade IV, case series) but found that intra-articular injections of MSCs reduced pain and improved function in patients with KOA over the short term, 1 year (Appendix 3).^19-25