Purpose
To perform a systematic review and meta-analysis evaluating the effects of mesenchymal
stem cells (MSCs) on cartilage regeneration and patient-reported pain and function.
Methods
A systematic review was conducted according to PRISMA (Preferred Reporting Items for
Systematic Reviews and Meta-Analyses) guidelines using a PRISMA checklist. The Cochrane
Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials,
PubMed (2008-2019), EMBASE (2008-2019), and MEDLINE (2008-2019) were queried in July
2019 for literature reporting use of stem cells to treat knee osteoarthritis or chondral
defects. Data describing administered treatment, subject population, injection type,
duration of follow-up, pain and functional outcomes, and radiographic and magnetic
resonance imaging findings were extracted. Risk of bias was assessed using the Downs
and Black scale. Meta-analyses adjusted for random effects were performed, calculating
pooled effect sizes in terms of patient-reported pain and function, cartilage quality,
and cartilage volume.
Results
Twenty-five studies with 439 subjects were identified. There was no significant difference
in pain improvement between MSC treatment and controls (pooled standardized mean difference
[SMD] = 0.23, P = .30). However, MSC treatment was significantly favored for functional improvement
(SMD = 0.66, P < .001). There was improvement in cartilage volume after MSC treatment (SMD = 0.84,
P < .001). Regarding cartilage quality, meta-analysis resulted in a small, nonsignificant
effect size of 0.37 (95%, –0.03 to 0.77, P = .07). There was risk for potential bias among included studies, with 17 (68%) receiving
either a grade of “poor” or “fair.”
Conclusions
The pooled SMD from meta-analyses showed statistically significant effects of MSC
on self-reported physical function but not self-reported pain. MSCs provided functional
benefit only in patients who underwent concomitant surgery. However, this must be
interpreted with caution, as there was substantial variability in MSC composition
and mode of delivery. MSC treatment provided significant improvement in cartilage
volume but not cartilage quality. Preliminary data regarding therapeutic properties
of MSC treatment suggest significant heterogeneity in the current literature, and
risk of bias is not negligible.
Level of Evidence
II, Systematic Review and Meta-analysis
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to ArthroscopyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Alternative methods for defining osteoarthritis and the impact on estimating prevalence in a US population-based survey.Arthritis Care Res (Hoboken). 2016; 68: 574-580
- Medical expenditures and earnings losses among us adults with arthritis in 2013.Arthritis Care Res (Hoboken). 2018; 70: 869-876
- National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, 2013: Statistical Brief #204. Healthcare Cost and Utilization Project (HCUP) Statistical Briefs.Agency for Healthcare Research and Quality (US), Rockville, MD2006
- Mesenchymal stem cells for the management of inflammation in osteoarthritis: State of the art and perspectives.Osteoarthritis Cartilage. 2015; 23: 2027-2035
- Efficacy of mesenchymal stem cells injection for the management of knee osteoarthritis: A systematic review and meta-analysis.Int Orthop. 2015; 39: 2363-2372
- Mechanisms involved in the therapeutic properties of mesenchymal stem cells.Cytokine Growth Factor Rev. 2009; 20: 419-427
- Efficacy of mesenchymal stem cells in treating patients with osteoarthritis of the knee: A meta-analysis.Exp Ther Med. 2016; 12: 3390-3400
- Effectiveness of mesenchymal stem cells for treating patients with knee osteoarthritis: A meta-analysis toward the establishment of effective regenerative rehabilitation.NPJ Regen Med. 2018; 3: 15
- Effect of mesenchymal stromal cells for articular cartilage degeneration treatment: A meta-analysis.Cytotherapy. 2015; 17: 1342-1352
- Clinical efficacy and safety of mesenchymal stem cell transplantation for osteoarthritis treatment: A meta-analysis.PLoS One. 2017; 12e0175449
- Magnetic resonance observation of cartilage repair tissue (MOCART) for the evaluation of autologous chondrocyte transplantation: Determination of interobserver variability and correlation to clinical outcome after 2 years.Eur J Radiol. 2006; 57: 16-23
- Whole-Organ Magnetic Resonance Imaging Score (WORMS) of the knee in osteoarthritis.Osteoarthritis Cartilage. 2004; 12: 177-190
- T2 texture index of cartilage can predict early symptomatic OA progression: Data from the osteoarthritis initiative.Osteoarthritis Cartilage. 2013; 21: 1550-1557
- Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement.BMJ. 2009; 339: b2535
- Measures of knee function: International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Form, Knee Injury and Osteoarthritis Outcome Score (KOOS), Knee Injury and Osteoarthritis Outcome Score Physical Function Short Form (KOOS-PS), Knee Outcome Survey Activities of Daily Living Scale (KOS-ADL), Lysholm Knee Scoring Scale, Oxford Knee Score (OKS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Activity Rating Scale (ARS), and Tegner Activity Score (TAS).Arthritis Care Res (Hoboken). 2011; 631 (suppl 11): S208-S228
- Intra-articular hyaluronic acid in treatment of knee osteoarthritis: A meta-analysis.JAMA. 2003; 290: 3115-3121
- OARSI Clinical Trials Recommendations: Design, conduct, and reporting of clinical trials for knee osteoarthritis.Osteoarthritis Cartilage. 2015; 23: 747-760
- The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions.J Epidemiol Community Health. 1998; 52: 377-384
- Risk factors and successful interventions for cricket-related low back pain: a systematic review.Br J Sports Med. 2014; 48: 685-691
- Are joint injury, sport activity, physical activity, obesity, or occupational activities predictors for osteoarthritis? A systematic review.J Orthop Sports Phys Ther. 2013; 43: 515-B519
- Gait modification strategies for altering medial knee joint load: A systematic review.Arthritis Care Res (Hoboken). 2011; 63: 405-426
- Failure of a numerical quality assessment scale to identify potential risk of bias in a systematic review: A comparison study.BMC Res Notes. 2015; 8: 224
- A power primer.Psychol Bull. 1992; 112: 155-159
- Review Manager (RevMan) [Computer program]. Version 5.3. The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen2014
- Matrix-induced autologous mesenchymal stem cell implantation versus matrix-induced autologous chondrocyte implantation in the treatment of chondral defects of the knee: A 2-year randomized study.Arch Orthop Trauma Surg. 2015; 135: 251-263
- Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®): Preclinical and clinical trial in osteoarthritis of the knee joint.Arthritis Res Ther. 2016; 18: 301
- The comparison of knee osteoarthritis treatment with single-dose bone marrow-derived mononuclear cells vs. hyaluronic acid injections.Medicina. 2017; 53
- Transplantation of autologous bone marrow-derived mesenchymal stem cells under arthroscopic surgery with microfracture versus microfracture alone for articular cartilage lesions in the knee: A multicenter prospective randomized control clinical trial.Regen Ther. 2019; 11: 106-113
- Comparative outcomes of open-wedge high tibial osteotomy with platelet-rich plasma alone or in combination with mesenchymal stem cell treatment: A prospective study.Arthroscopy. 2014; 30: 1453-1460
- Adipose-derived mesenchymal stem cells with microfracture versus microfracture alone: 2-year follow-up of a prospective randomized trial.Arthroscopy. 2016; 32: 97-109
- Safety, tolerability and efficacy of intra-articular Progenza in knee osteoarthritis: A randomized double-blind placebo-controlled single ascending dose study.J Transl Med. 2018; 16: 49
- 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 Transl Med. 2019; 8: 504-511
- Treatment of knee osteoarthritis with intra-articular injection of autologous adipose-derived mesenchymal progenitor cells: A prospective, randomized, double-blind, active-controlled, phase IIb clinical trial.Stem Cell Res Ther. 2019; 10: 143
- Avoidance of total knee arthroplasty in early osteoarthritis of the knee with intra-articular implantation of autologous activated peripheral blood stem cells versus hyaluronic acid: A randomized controlled trial with differential effects of growth factor addition.Stem Cells Int. 2017; 2017: 10
- Injectable cultured bone marrow–derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: A prospective, randomized controlled clinical trial with 2 years' follow-up.Arthroscopy. 2013; 29: 2020-2028
- Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: A randomized controlled trial.Transplantation. 2015; 99: 1681-1690
- Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees.Osteoarthritis Cartilage. 2002; 10: 199-206
- Intra-articular injection of expanded autologous bone marrow mesenchymal cells in moderate and severe knee osteoarthritis is safe: A phase I/II study.J Orthop Surg Res. 2017; 12: 190
- Bone marrow mesenchymal stromal cell treatment in patients with osteoarthritis results in overall improvement in pain and symptoms and reduces synovial inflammation.Stem Cells Transl Med. 2019; 8: 746-757
- Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: A proof-of-concept clinical trial.Stem Cells. 2014; 32: 1254-1266
- Mesenchymal stem cell implantation in osteoarthritic knees: Is fibrin glue effective as a scaffold?.Am J Sports Med. 2014; 43: 176-185
- Comparative matched-pair analysis of open-wedge high tibial osteotomy with versus without an injection of adipose-derived mesenchymal stem cells for varus knee osteoarthritis: Clinical and second-look arthroscopic results.Am J Sports Med. 2018; 46: 2669-2677
- Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: A phase I dose-escalation trial.Stem Cells Transl Med. 2016; 5: 847-856
- Cartilage regeneration in osteoarthritic patients by a composite of allogeneic umbilical cord blood-derived mesenchymal stem cells and hyaluronate hydrogel: Results from a clinical trial for safety and proof-of-concept with 7 years of extended follow-up.Stem Cells Transl Med. 2017; 6: 613-621
- Intra-articular injection of autologous adipose-derived mesenchymal stem cells in the treatment of knee osteoarthritis.J Gene Med. 2018; 20e3002
- Human adipose-derived mesenchymal stem cells for osteoarthritis: A pilot study with long-term follow-up and repeated injections.Regen Med. 2018; 13: 295-307
- Assessment of clinical and MRI outcomes after mesenchymal stem cell implantation in patients with knee osteoarthritis: a prospective study.Osteoarthritis Cartilage. 2016; 24: 237-245
- Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis.Knee. 2012; 19: 902-907
- Comparative matched-pair analysis of the injection versus implantation of mesenchymal stem cells for knee osteoarthritis.Am J Sports Med. 2015; 43: 2738-2746
- Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: A 2-year follow-up study.Am J Sports Med. 2017; 45: 2774-2783
- The new avenues in the management of osteo-arthritis of knee-stem cells.J Indian Med Assoc. 2010; 108: 583-585
- Enhanced medial collateral ligament healing using mesenchymal stem cells: Dosage effects on cellular response and cytokine profile.Stem Cell Rev Rep. 2014; 10: 86-96
- Responsiveness of the International Knee Documentation Committee Subjective Knee Form in comparison to the Western Ontario and McMaster Universities Osteoarthritis Index, modified Cincinnati Knee Rating System, and Short Form 36 in patients with focal articular cartilage defects.Am J Sports Med. 2010; 38: 891-902
- Evaluation of clinically relevant changes in patient reported outcomes in knee and hip osteoarthritis: The minimal clinically important improvement.Ann Rheum Dis. 2005; 64: 29-33
- Factors associated with clinically significant patient-reported outcomes after primary arthroscopic partial meniscectomy.Arthroscopy. 2019; 35: 1567-1575 e1563
- How to define subregional osteoarthritis progression using semi-quantitative MRI Osteoarthritis Knee Score (MOAKS).Osteoarthritis Cartilage. 2014; 22: 1533-1536
- Quantitative assessment of barriers to the clinical development and adoption of cellular therapies: A pilot study.J Tissue Engineering. 2014; 5 (2041731414551764)
Article info
Publication history
Published online: June 01, 2020
Accepted:
May 17,
2020
Received:
January 24,
2020
Footnotes
See commentary on page 379
The authors report the following potential conflicts of interest or sources of funding: B.J.C. reports grants, personal fees, and nonfinancial support from Arthrex, during the conduct of the study; and other from Aesculap, other from Athletico, personal fees from Elsevier Publishing, other from JRF Orthro, other from the National Institutes of Health, personal fees and other from OSTM, personal fees from Ossio, personal fees and other from Regentis, and other from Smith & Nephew, outside the submitted work. J.C. is an unpaid consultant for Arthrex, Smith & Nephew, and CONMED Linvatec. N.N.V. reports personal fees and other from Arthrex, personal fees and other from Arthroscopy, personal fees from Breg, personal fees from Minivasive, personal fees from Orthospace, personal fees from Ossur, personal fees and other from Smith & Nephew, personal fees and other from Vindico Medical-Orthopedics Hyperguide, and personal fees from Wright Medical Technology, outside the submitted work. N.N.V. is on the editorial or governing board of the following organizations: American Orthopaedic Society for Sports Medicine, American Shoulder and Elbow Surgeons, Arthroscopy Association of North America, KNEE, and Slack Incorporated. A.Y. reports grants from Vericel, grants from OREF, grants from Arthrex, other from Patient IQ, other from Smith & Nephew, other from Sparta Biomedical, other from JRF, and other from Olympus, outside the submitted work. Full ICMJE author disclosure forms are available for this article online, as supplementary material.
Identification
Copyright
© 2020 by the Arthroscopy Association of North America
