Systematic Review
Regenerative Potential of Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis and Chondral Defects: A Systematic Review and Meta-analysis

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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

Section snippets

Article Identification and Selection

This study was conducted in accordance with the 2009 Preferred Reporting Items for Systematic Review and Meta-Analysis statement (Fig 1).14 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 on the use of stem cells to treat OA or chondral defects of the knee. Database queries were performed using the following Boolean search terms:

Study Characteristics

The database query yielded a total of 3585 studies, of which 25 studies satisfied all prespecified inclusion criteria. Because of extensive cross referencing and confirmation that no study data were replicated in included studies, there was no potential for duplicate data on the same patients across studies. Study characteristics of all studies, including those not used for meta-analyses, are described in Tables 1 and 2.25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,

Discussion

The main findings of the current study are as follows: (1) the majority of studies reported improvements in patient-reported pain and physical function following MSC interventions; however, meta-analyses found that only self-reported physical function significantly improved relative from controls; (2) MSC treatment results in significant improvement in cartilage volume, but not cartilage quality, relative to controls; and (3) there is limited evidence in the current literature to support

Conclusions

In conclusion, the pooled standard mean difference 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

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    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.

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