Research

Orthopedic

A multitude of research has been published clearly demonstrating the safety and effectiveness of stem cell therapy in the treatment of orthopedic conditions. Stem cell therapy has been shown to reduce pain and pain medication requirement, improve function, increase range of motion, increase cartilage volume, and more.

Based on the early human clinical trials there appears to be a strong argument for the safe and effective use of stem cell therapy in the treatment of orthopedic conditions. While we wait for phase II/III trials the current data is encouraging and supports use of stem cell therapy in the clinical setting.

Below we highlight and summarize selected studies demonstrating the safety and efficacy of stem cell therapy in orthopedic conditions. All of the selected studies used intra-articular or soft tissue injections but used different cell types and tissue types. We also include systematic reviews/meta-analysis for additional evidence.

VARIOUS ORTHOPEDIC CONDITIONS:

In 2016 Centeno et al conducted a multicenter analysis of over 2000 patients who received stem cell therapy for various orthopedic conditions involving multiple affected joints. The therapy was deemed safe and well tolerated with low rates of reported adverse events and substantially lower rates of serious or treatment related adverse events.

KNEE:

A randomized controlled trial by Freitag et al to assess the efficacy of adipose derived mesenchymal stem cells (ADMSCs) in knee osteoarthritis (OA) revealed no serious adverse events and statistically and clinically significant improvements in pain and function as measured by common assessments including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Knee Injury Osteoarthritis Outcome Score (KOOS). A double blind randomized controlled trial by Lee et al assessing efficacy of ADMSCs in patients with knee OA also showed significant improvement in pain and function measured by visual analog pain scale (VAS), KOOS and WOMAC scores as well as stabilization of cartilage defects without any serious adverse events. Similarly, Pers at el demonstrated that injection with ADMSCs in patients with knee OA improved pain and function as measured by VAS, WOMAC and KOOS scores without adverse events. A proof of concept trial by Jo et al assessing safety and efficacy of ADMSCs in patients with knee OA showed improvement in WOMAC and VAS scores and increased cartilage volume and regeneration of articular cartilage without treatment related adverse events.

Hong et al showed patients with knee OA treated with adipose derived stromal vascular fraction (ADSVF) had significant improvements in pain and function measured by WOMAC scores and visual analog pain scale (VAS) and in cartilage repair on MRI. No severe adverse events were observed during 12 month follow up. Results from a preliminary clinical study by Bansal et al, assessing adipose derived stromal vascular fraction (ADSVF) with platelet rich plasma (PRP) for knee OA show significant reductions in WOMAC scores, improvement in cartilage thickness, statistically significant improvement in 6 minute walking distance and a decrease in required pain medication. Japanese Knee Osteoarthritis Measure (JKOM), WOMAC and VAS were significantly improved at 6 month follow up in patients who received ADSVF injections for knee OA in a prospective, uncontrolled study by Yokota et al.

A randomized, controlled trial by Matas et al to assess umbilical cord derived mesenchymal stem cells (UCMSCs) in patients with knee OA showed significant reductions in WOMAC and VAS scores at 6 and 12 months without serious adverse events.

A systematic review and meta-analysis by Iijima et al of 35 studies involving over 2000 patients with knee osteoarthritis found that stem cell therapy reduced pain as measured by VAS and improved self-reported physical function and cartilage volume and quality.

HIP:

Mardones et al assessed the efficacy of multiple stem cell injections in patients with osteoarthritis and cartilage defects in the hip. They observed improvement in radiographic scores, hip range of motion and function during follow up period. They concluded that stem cell therapy proved to be safe and clinically effective for osteoarthritis of the hip.

BACK:

Sanapati et al conducted a systematic review of 21 studies to assess the effectiveness of PRP and stem cell therapy in the treatment of low back and lower extremity pain. Their data shows that both stem cell therapy and PRP may be effective in managing local and radiating low back pain originating from intervertebral discs, facet joints and sacroiliac joints. Centeno et al performed a proof of concept study to assess the safety and efficacy of bone marrow derived mesenchymal stem cells in thirty-three patients with lower back pain and disc degeneration with disc bulge. Patients were followed up to 6 years post treatment. Their results show patients reported minor adverse events and had significant improvements in pain, function, and overall subjective improvement. In addition, 85% of patients who underwent post treatment MRI had a reduction in disc bulge size.

HAND:

Murphy et al assessed the efficacy of stem cell therapy in osteoarthritis of the thumb. They observed significant improvements in pain at rest and during activity, range of motion and strength during 12 month follow up. They also found that all patients who had a positive grind test at baseline had a negative grind test at 12 months.

SHOULDER:

Hernigou et al performed a clinical study comparing the rotator cuff repair with and without bone marrow derived mesenchymal stem cells (BMMSCs). Patients treated with stem cells had superior tendon healing and superior quality of the repaired tendon. Healing was demonstrated in 100% of shoulders treated with stem cells at 6 months. At 10 year follow up 87% of repairs were intact in stem cell group compared to 44% in control group. Kim et al conducted a prospective, nonrandomized study to compare bone marrow aspirate concentration (BMAC)-PRP injections vs shoulder physical therapy in patients with partial rotator cuff tears. After 3 months pain and functional outcome scores were significantly improved in injection group however there were no changes in tear size between groups. Centeno et al performed a prospective multicenter study to investigate the efficacy of bone marrow aspirate concentration (BMAC) in patients with shoulder osteoarthritis with or without rotator cuff tears. Pain and functional outcome scores were significantly improved at 1 month and up to 2 years. Kim et al assessed the clinical and MRI outcomes following rotator cuff repair with or without adipose derived mesenchymal stem cells (ADMSCs). Significant improvements were observed in both groups 2 years after treatment. Patients treated with stem cells had a lower rate of failed healing compared to control group at 1 year follow up. Similarly, Jo et al conducted a clinical study to assess the effects of adipose derived mesenchymal stem cells (ADMSCs) in patients with partial thickness rotator cuff tears. Treatment with stem cells significantly reduced shoulder pain, improved clinical outcome scores and reduced bursal-sided defect up 90%.

In addition to stem cell therapy, other regenerative treatments for orthopedic conditions including platelet rich plasma, prolozone therapy, etc., are commonly used. Non-injection based supportive treatments are also important to maximize effects of regenerative therapies. This includes nutritional intravenous therapy, natural supplements, bio-identical hormone replacement, peptide therapy and more.

SOURCES OF SELECTED STUDIES:

• Centeno, C. J., Al-Sayegh, H., Freeman, M. D., Smith, J., Murrell, W. D., & Bubnov, R. (2016). A multi-center analysis of adverse events among two thousand, three hundred and seventy two adult patients undergoing adult autologous stem cell therapy for orthopaedic conditions. International Orthopaedics, 40(8), 1755–1765. https://doi.org/10.1007/s00264-016-3162-y
• Freitag, J., Bates, D., Wickham, J., Shah, K., Huguenin, L., Tenen, A., … Boyd, R. (2019). Adipose-derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis: A randomized controlled trial. Regenerative Medicine, 14(3), 213–230. https://doi.org/10.2217/rme-2018-0161
• Hong, Z., Chen, J., Zhang, S., Zhao, C., Bi, M., Chen, X., & Bi, Q. (2019). Intra-articular injection of autologous adipose-derived stromal vascular fractions for knee osteoarthritis: a double-blind randomized self-controlled trial. International Orthopaedics, 43(5), 1123–1134. https://doi.org/10.1007/s00264-018-4099-0
• Lee, W. S., Kim, H. J., Kim, K. Il, Kim, G. B., & Jin, W. (2019). Intra-Articular Injection of Autologous Adipose Tissue-Derived Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis: A Phase IIb, Randomized, Placebo-Controlled Clinical Trial. Stem Cells Translational Medicine, 8(6), 504–511. https://doi.org/10.1002/sctm.18-0122
• Pers, Y.-M., Rackwitz, L., Ferreira, R., Pullig, O., Delfour, C., Barry, F., … Jorgensen, C. (2016). Adipose Mesenchymal Stromal Cell-Based Therapy for Severe Osteoarthritis of the Knee: A Phase I Dose-Escalation Trial. STEM CELLS Translational Medicine. https://doi.org/10.5966/sctm.2015-0245
• Matas, J., Orrego, M., Amenabar, D., Infante, C., Tapia-Limonchi, R., Cadiz, M. I., … Espinoza, F. (2019). Umbilical Cord-Derived Mesenchymal Stromal Cells (MSCs) for Knee Osteoarthritis: Repeated MSC Dosing Is Superior to a Single MSC Dose and to Hyaluronic Acid in a Controlled Randomized Phase I/II Trial. Stem Cells Translational Medicine, 8(3), 215–224. https://doi.org/10.1002/sctm.18-0053
• Bansal, H., Comella, K., Leon, J., Verma, P., Agrawal, D., Koka, P., & Ichim, T. (2017). Intra-articular injection in the knee of adipose derived stromal cells (stromal vascular fraction) and platelet rich plasma for osteoarthritis. Journal of Translational Medicine. https://doi.org/10.1186/s12967-017-1242-4
• Jo, C. H., Chai, J. W., Jeong, E. C., Oh, S., Shin, J. S., Shim, H., & Yoon, K. S. (2017). Intra-articular Injection of Mesenchymal Stem Cells for the Treatment of Osteoarthritis of the Knee: A 2-Year Follow-up Study. The American Journal of Sports Medicine, 45(12), 2774–2783. https://doi.org/10.1177/0363546517716641
• Yokota, N., Yamakawa, M., Shirata, T., Kimura, T., & Kaneshima, H. (2017). Clinical results following intra-articular injection of adipose-derived stromal vascular fraction cells in patients with osteoarthritis of the knee. Regenerative Therapy, 6, 108–112. https://doi.org/10.1016/j.reth.2017.04.002
• Iijima, H., Isho, T., Kuroki, H., Takahashi, M., & Aoyama, T. (2018). Effectiveness of mesenchymal stem cells for treating patients with knee osteoarthritis: a meta-analysis toward the establishment of effective regenerative rehabilitation. Npj Regenerative Medicine, 3(1). https://doi.org/10.1038/s41536-018-0041-8
• Mardones, R., Jofré, C. M., Tobar, L., & Minguell, J. J. (2017). Mesenchymal stem cell therapy in the treatment of hip osteoarthritis. Journal of Hip Preservation Surgery, 4(2), 159–163. https://doi.org/10.1093/jhps/hnx011
• Sanapati, J., Manchikanti, L., Atluri, S., Jordan, S., Albers, S. L., Pappolla, M. A., … Hirsch, J. A. (2018). Do Regenerative Medicine Therapies Provide Long-Term Relief in Chronic Low Back Pain: A Systematic Review and Metaanalysis. Pain Physician, 21(6), 515–540. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/30508983
• Centeno, C., Markle, J., Dodson, E., Stemper, I., Williams, C. J., Hyzy, M., … Freeman, M. (2017). Treatment of lumbar degenerative disc disease-associated radicular pain with culture-expanded autologous mesenchymal stem cells: A pilot study on safety and efficacy. Journal of Translational Medicine, 15(1). https://doi.org/10.1186/s12967-017-1300-y
• Murphy, M. P., Buckley, C., Sugrue, C., Carr, E., O’Reilly, A., O’Neill, S., & Carroll, S. M. (2017). ASCOT: Autologous Bone Marrow Stem Cell Use for Osteoarthritis of the Thumb – First Carpometacarpal Joint. Plastic and Reconstructive Surgery – Global Open, 5(9). https://doi.org/10.1097/GOX.0000000000001486
• Hernigou P, Flouzat Lachaniette CH, Delambre J, Zilber S, Duffiet P, Chevallier N, et al. Biologic augmentation of rotator cuff repair with mesenchymal stem cells during arthroscopy improves healing and prevents further tears: a case-controlled study. Int Orthop 2014;38: 1811-8. https://doi.org/10.1007/s00264-014-2391-1
• Kim SJ, Kim EK, Kim SJ, Song DH. Effects of bone marrow aspirate concentrate and platelet-rich plasma on patients with partial tear of the rotator cuff tendon. J Orthop Surg Res 2018;13:1. https://doi.org/ 10.1186/s13018-017-0693-x
• Centeno CJ, Al-Sayegh H, Bashir J, Goodyear SH, Freeman MD. A prospective multi-site registry study of a specific protocol of autologous bone marrow concentrate for the treatment of shoulder rotator cuff tears and osteoarthritis. J Pain Res 2015;8:269-76. https://doi.org/10.2147/JPR.S80872
• Kim YS, Sung CH, Chung SH, Kwak SJ, Koh YG. Does an injection of adipose-derived mesenchymal stem cells loaded in fibrin glue influence rotator cuff repair outcomes? A clinical and magnetic resonance imaging study. Am J Sports Med 2017;45:2010-8. https://doi.org/10.1177/0363546517702863
• Jo CH, Chai JW, Jeong EC, Oh S, Kim PS, Yoon JY, et al. Intra- tendinous injection of autologous adipose tissue-derived mesen- chymal stem cells for the treatment of rotator cuff disease: a first-in- human trial. Stem Cells 2018;36:1441-50. https://doi.org/10.1002/stem.2855