Osteoarthritis and stem cell therapy in humans: a systematic review

D.S. Jevotovsky; A.R. Alfonso; T.A. Einhorn; E.S. Chiu

doi:10.1016/j.joca.2018.02.906

Osteoarthritis and stem cell therapy in humans: a systematic review

D.S. Jevotovsky
D.S. Jevotovsky
Correspondence
Address correspondence and reprint requests to: D.S. Jevotovsky, Department of Orthopaedic Surgery, NYU Langone Health, New York, NY, USA.
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Affiliations
Department of Orthopaedic Surgery, NYU Langone Health, New York, NY, USA
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A.R. Alfonso
A.R. Alfonso
Affiliations
Hansjörg Wyss Department of Plastic Surgery, NYU Langone Health, New York, NY, USA
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T.A. Einhorn
T.A. Einhorn
Affiliations
Department of Orthopaedic Surgery, NYU Langone Health, New York, NY, USA
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E.S. Chiu
E.S. Chiu
Correspondence
Address correspondence and reprint requests to: E.S. Chiu, Hansjörg Wyss Department of Plastic Surgery, NYU Langone Health, New York, NY, USA.
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Hansjörg Wyss Department of Plastic Surgery, NYU Langone Health, New York, NY, USA
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Open ArchivePublished:March 12, 2018DOI:https://doi.org/10.1016/j.joca.2018.02.906

Summary

Objective

Osteoarthritis (OA) is a leading cause of disability in the world. Mesenchymal stem cells (MSCs) have been studied to treat OA. This review was performed to systematically assess the quality of literature and compare the procedural specifics surrounding MSC therapy for osteoarthritis.

Design

PubMed, CINAHL, EMBASE and Cochrane Central Register of Controlled Trials were searched for studies using MSCs for OA treatment (final search December 2017). Outcomes of interest included study evidence level, patient demographics, MSC protocol, treatment results and adverse events. Level I and II evidence articles were further analyzed.

Results

Sixty-one of 3,172 articles were identified. These studies treated 2,390 patients with osteoarthritis. Most used adipose-derived stem cells (ADSCs) (n = 29) or bone marrow-derived stem cells (BMSCs) (n = 30) though the preparation varied within group. 57% of the sixty-one studies were level IV evidence, leaving five level I and nine level II studies containing 288 patients to be further analyzed. Eight studies used BMSCs, five ADSCs and one peripheral blood stem cells (PBSCs). The risk of bias in these studies showed five level I studies at low risk with seven level II at moderate and two at high risk.

Conclusion

While studies support the notion that MSC therapy has a positive effect on OA patients, there is limited high quality evidence and long-term follow-up. The present study summarizes the specifics of high level evidence studies and identifies a lack of consistency, including a diversity of MSC preparations, and thus a lack of reproducibility amongst these articles’ methods.

Keywords

Introduction

Osteoarthritis (OA) is the most common joint disorder in the world and the most common arthritis in the United States

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To date, few MSC-related adverse events have been noted

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The International Society for Cellular Therapy developed criteria to define MSCs as plastic-adherent in culture conditions expressing CD105, CD73, and CD90, lacking expression of CD45, CD34, CD14 or CD11b, CD79alpha or CD19, and HLA-DR surface molecules, and possessing tri-lineage differentiation into osteoblasts, adipocytes and chondroblasts

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. Once removed, typically from the iliac crest, BMSCs can be expanded in culture and induced to various stages of differentiation

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. Adipose tissue is abundant, making ADSC procurement easy and minimally invasive

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Alfonso Z.
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. These cells are harvested from infra-patellar fat pads or subcutaneous sites such as the buttocks

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or after subcutaneous administration of human granulocyte colony stimulating factor prior to blood draw

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.

The above MSCs can be isolated, culture-expanded and subsequently injected into joints. Other intra-articular formulations with one-step harvest and injection procedures are becoming popular, including injection of bone marrow aspirate concentrate (BMAC) containing BMSCs, stromal vascular fraction (SVF) isolated from lipoaspirate containing ADSCs, and microfragmented adipose tissue, a non-enzymatic approach to isolating the stromal vascular niche with ADSCs. SVF is isolated via liposuction, followed by collagenase digestion, centrifugation, and dilution

²⁵

Zuk P.A.
Zhu M.
Ashjian P.
De Ugarte D.A.
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Mizuno H.
et al.

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^,

³⁵

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Geiger H.

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Kang L.W.
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Current use of autologous adipose tissue-derived stromal vascular fraction cells for orthopedic applications.

. BMAC contains a mixture of platelets, red and white blood cells, and hematopoietic and non-hematopoietic precursors. The term refers to the mixture of marrow elements and MSCs, but, after processing, only 0.001–0.01% of the cells are MSCs

³⁷

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Chubinskaya S.

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. The SVF product contains MSCs, pericytes, fibroblasts, monocytes and macrophages, with 500,000 to 2,00,000 cells per gram of which 1–10% are considered ADSCs

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Baer P.C.
Geiger H.

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³⁶

Pak J.
Lee J.H.
Park K.S.
Park M.
Kang L.W.
Lee S.H.

Current use of autologous adipose tissue-derived stromal vascular fraction cells for orthopedic applications.

. Microfragmented adipose tissue is obtained by harvesting lipoaspirate and washing off residues while adipose cluster dimensions are gradually reduced. Initial analysis has shown it contains preserved stromal vascular architecture with pericytes and MSCs

³⁸

Tremolada C.
Colombo V.
Ventura C.

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.

Although MSC therapy has been used to treat articular cartilage repair for years, few clinical studies provide satisfactory levels of evidence to address the quality of available information. The Journal of Bone and Joint Surgery's (JBJS) Levels of Evidence rating scale defines parameters to help authors make level of evidence evaluations (level I, randomized controlled trial; level II, prospective cohort study or observational study with dramatic effect; level III, retrospective cohort study or case–control study; level IV, case series; level V, mechanism-based reasoning)

³⁹

Marx R.G.
Wilson S.M.
Swiontkowski M.F.

Updating the assignment of levels of evidence.

. These parameters help inform physicians' clinical decisions.

To our knowledge, there has been no systematic review which analyzes the effect of study quality and procedural specifics of both autologous and allogeneic MSC therapy for the treatment of OA. The aims of this investigation are to provide an analysis of the literature regarding the use of MSC therapy for OA treatment, to assess the quality of evidence, and to propose next steps for further investigation.

Methods

Search strategy

This review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines

⁴⁰

Moher D.
Liberati A.
Tetzlaff J.
Altman D.G.

Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.

. A literature search identified all articles involving stem cell therapy to treat osteoarthitis. PubMed, CINAHL, EMBASE and Cochrane Central Register of Controlled Trials were searched using “osteoarthritis” and “stem cell” MeSH terms presented in further detail in the appendix. Computer de-duplication was performed. The search was finalized in December 2017. Manual review of the references of selected articles was also completed to add studies that were originally missed.

Study selection

Two reviewers (DJ and AA) independently evaluated studies. Third and fourth reviewers (TE and EC) resolved any discrepancies for inclusion. After identifying the relevant studies through abstract information, studies were included after full-text evaluation. Inclusion criteria was any clinical study that used stem cells to treat osteoarthritis in humans. Outcome measures varied amongst articles. These measures included safety analyzed by the nature of adverse events, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Visual Analogue Scale (VAS) for pain, radiographic MRI or X-ray scores, as well as several others. Articles from any country were acceptable but limited to those published in the English language. Exclusion criteria were articles that did not use MSCs to directly treat OA patients, that were reviews, conference submissions/abstracts only or letters to the editor, that studied stem cells in vitro, that studied isolated, focal chondral defects not associated with OA, and that presented their research in a language other than English.

Data extraction and assessment of study quality

Authors (DJ and AA) independently extracted data using a template data extraction sheet, with third and fourth researchers (TE and EC) serving as tiebreakers if consensus was not achieved. Information gathered included study characteristics, patient demographics and outcomes. Primary outcome was the improvement, or lack thereof, in the patients' OA. Studies were rated on methodological quality according to The JBJS Levels of Evidence rating scale

³⁹

Marx R.G.
Wilson S.M.
Swiontkowski M.F.

Updating the assignment of levels of evidence.

. Risk of bias assessment was completed to evaluate each study's internal validity using Cochrane's Risk of Bias scale for randomized trials (RoB2.0)

⁴¹

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and Risk of Bias In Non-randomised Studies – of Intervention (ROBINS-I) tool

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.

Analysis

Because of overall study heterogeneity and lack of adequate control groups, a formal statistical meta-analysis was attempted but not performed; however, pooled rates of several collected measures were calculated with the available data using Microsoft Excel when applicable.

Results

Literature search

The initial search of the three databases yielded a total of 3,416 articles. Nine articles were identified through other sources. Duplicates were removed and 3,172 articles remained. Of these articles, 381 were selected as relevant to the application of stem cell therapy for OA treatment. Of those articles, 61 were chosen to be discussed in this review due to their clinical nature. The PRISMA flow diagram can be visualized in Fig. 1. According to Marx, Wilson and Swiontkowski (2015), five studies classified as level I evidence, nine as level II, seven as level III, thirty-five as level IV, and five as level V.

Figure thumbnail gr1 — Fig. 1Osteoarthritis and stem cell therapy PRISMA flow diagram.
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Levels I–V (all clinical studies): study characteristics and intervention details

In total, the 61 studies enrolled 2,390 OA patients to be treated with MSC therapy. Table I gives an overview of study characteristics, while Table II

¹³

Jo C.H.
Lee Y.G.
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Kim H.
Chai J.W.
Jeong E.C.
et al.

Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial.

^,

²⁹

Garay-Mendoza D.
Villarreal-Martinez L.
Garza-Bedolla A.
Perez-Garza D.M.
Acosta-Olivo C.
Vilchez-Cavazos F.
et al.

The effect of intra-articular injection of autologous bone marrow stem cells on pain and knee function in patients with osteoarthritis.

^,

³⁰

Nguyen P.D.
Tran T.D.
Nguyen H.T.
Vu H.T.
Le P.T.
Phan N.L.
et al.

Comparative clinical observation of arthroscopic microfracture in the presence and absence of a stromal vascular fraction injection for osteoarthritis.

^,

⁴³

Ahmad K.A.
Ibrahim Y.A.
Saber N.Z.
Darwish B.A.

MR cartilage imaging in assessment of the regenerative power of autologous peripheral blood stem cell injection in knee osteoarthritis.

^,

⁴⁴

Bansal H.
Comella K.
Leon J.
Verma P.
Agrawal D.
Koka P.
et al.

Intra-articular injection in the knee of adipose derived stromal cells (stromal vascular fraction) and platelet rich plasma for osteoarthritis.

^,

⁴⁵

Buda R.
Castagnini F.
Cavallo M.
Ramponi L.
Vannini F.
Giannini S.

One-step" bone marrow-derived cells transplantation and joint debridement for osteochondral lesions of the talus in ankle osteoarthritis: clinical and radiological outcomes at 36 months.

^,

⁴⁶

Centeno C.
Pitts J.
Al-Sayegh H.
Freeman M.

Efficacy of autologous bone marrow concentrate for knee osteoarthritis with and without adipose graft.

^,

⁴⁷

Centeno C.J.
Al-Sayegh H.
Bashir J.
Goodyear S.
Freeman M.D.

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.

^,

⁴⁸

Centeno C.J.
Al-Sayegh H.
Bashir J.
Goodyear S.
Freeman M.D.

A dose response analysis of a specific bone marrow concentrate treatment protocol for knee osteoarthritis.

^,

⁴⁹

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Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells, platelet lysate and dexamethasone.

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Keohan C.
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Karli D.

Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells.

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⁵¹

Centeno C.J.
Busse D.
Kisiday J.
Keohan C.
Freeman M.
Karli D.

Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells.

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⁵²

Centeno C.J.
Schultz J.R.
Cheever M.
Freeman M.
Faulkner S.
Robinson B.
et al.

Safety and complications reporting update on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique.

^,

⁵³

Davatchi F.
Abdollahi B.S.
Mohyeddin M.
Shahram F.
Nikbin B.

Mesenchymal stem cell therapy for knee osteoarthritis. Preliminary report of four patients.

^,

⁵⁴

Davatchi F.
Sadeghi Abdollahi B.
Mohyeddin M.
Nikbin B.

Mesenchymal stem cell therapy for knee osteoarthritis: 5 years follow-up of three patients.

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Emadedin M.
Ghorbani Liastani M.
Fazeli R.
Mohseni F.
Moghadasali R.
Mardpour S.
et al.

Long-term follow-up of intra-articular injection of autologous mesenchymal stem cells in patients with knee, Ankle, or Hip Osteoarthritis.

^,

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provides individual study details organized by level of evidence. Of the total study population, 2,662 joints were treated and 46% were female (N = 1095). OA sites included knee (51 studies), hand (2 studies), ankle (3 studies), shoulder (1 study), hip (2 studies) or multiple joints (2 studies with knee, hip and ankle).

Table IOverview of the included clinical studies

N ^∗ Number of patients treated with stem cell therapy. (male/female)	OA site		MSC type ^† 2 studies used both SVF/ADSC and BMAC/BMSC26,57.			Levels of evidence ^‡ Levels of evidence according to Marx, Wilson, & Swiontkowski (2015)56.
2,390 (1095/1315) ^§ Based on total number of joints of those studies that reported gender (6 studies did not report gender by joint)72,81,85,95,82.	Knee	51	ADSC 29	CE	3	I	5
	Ankle	3		SVF	24	II	9
	Ankle	3		Micro	2	II	9
	Hand	2	BMSC 30	CE	18	III	7
	Shoulder	1		BMAC	10	IV	35
	Hip	2		Allog			2
	Multiple Knee/Hip/Ankle	2	PBSC	3		V	5
	Multiple Knee/Hip/Ankle	2	Allog hUCB-MSCs	1		V	5

ADSC = adipose-derived stem cell; BMSC = bone-marrow stem cell; MSC = mesenchymal stem cell; OA = osteoarthritis; PBSC = peripheral blood stem cell.

CE: culture-expanded; Allog: allogeneic; Micro: microfragmented; hUCB-MSCs: human umbilical cord blood-derived mesenchymal stem cells.

∗ Number of patients treated with stem cell therapy.

† 2 studies used both SVF/ADSC and BMAC/BMSC

²⁶

Kim Y.S.
Choi Y.J.
Koh Y.G.

Mesenchymal stem cell implantation in knee osteoarthritis: an assessment of the factors influencing clinical outcomes.

^,

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Gibbs N.
Diamond R.
Sekyere E.O.
Thomas W.D.

Management of knee osteoarthritis by combined stromal vascular fraction cell therapy, platelet-rich plasma, and musculoskeletal exercises: a case series.

.

‡ Levels of evidence according to Marx, Wilson, & Swiontkowski (2015)

⁵⁶

Fodor P.B.
Paulseth S.G.

Adipose derived stromal cell (ADSC) injections for pain management of osteoarthritis in the human knee joint.

.

§ Based on total number of joints of those studies that reported gender (6 studies did not report gender by joint)

⁷²

Orozco L.
Munar A.
Soler R.
Alberca M.
Soler F.
Huguet M.
et al.

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Varma H.S.
Dadarya B.
Vidyarthi A.

The new avenues in the management of osteo-arthritis of knee - stem cells.

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Wakitani S.
Imoto K.
Yamamoto T.
Saito M.
Murata N.
Yoneda M.

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^,

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Wakitani S.
Okabe T.
Horibe S.
Mitsuoka T.
Saito M.
Koyama T.
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Safety of autologous bone marrow-derived mesenchymal stem cell transplantation for cartilage repair in 41 patients with 45 joints followed for up to 11 years and 5 months.

.

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Table IIStudy characteristics of the included clinical studies grouped by level of evidence

First Author (Date of publication)	Country of origin	Level of evidence ⁵⁶ Fodor P.B. Paulseth S.G. Adipose derived stromal cell (ADSC) injections for pain management of osteoarthritis in the human knee joint. Aesthetic Surg J. 2016 Feb; 36: 229-236 Crossref PubMed Scopus (95) Google Scholar	N ^∗ N = number of patients in the treatment group. (Male/Female)	OA site	MSC Source/Type	Biologic adjuvant	Outcome measures	Follow-up length of time
Garay-Mendoza (2017) ²⁹ Garay-Mendoza D. Villarreal-Martinez L. Garza-Bedolla A. Perez-Garza D.M. Acosta-Olivo C. Vilchez-Cavazos F. et al. The effect of intra-articular injection of autologous bone marrow stem cells on pain and knee function in patients with osteoarthritis. Int J Rheum Dis. 2017 Jul 27; 21: 140-147 Crossref PubMed Scopus (49) Google Scholar	Mexico	I	30 (7/23)	Knee	BMAC/BMSC	Outpatient SQ G-CSF x 3 days	VAS WOMAC	6 mo
Gupta (2016) ⁸⁹ Gupta P.K. Chullikana A. Rengasamy M. Shetty N. Pandey V. Agarwal V. et al. Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel(R)): preclinical and clinical trial in osteoarthritis of the knee joint. Arthritis Res Ther. 2016 Dec 20; 18: 301 Crossref PubMed Scopus (181) Google Scholar	India	I	40 (12/28)	Knee	Allogeneic culture-expanded BMSC	PLASMALYTE-A Pre: Hydrocortisone and pheniramine maleate Post: Hyaluronic acid	VAS for pain ICOAP WOMAC WORMS – knee	12 mo
Lamo-Espinosa (2016) ⁸⁷ Lamo-Espinosa J.M. Mora G. Blanco J.F. Granero-Molto F. Nunez-Cordoba J.M. Sanchez-Echenique C. et al. Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II). J Transl Med. 2016 Aug 26; 14: 246 Crossref PubMed Scopus (184) Google Scholar	Spain	I	20 (12/8)	Knee	Culture-expanded BMSC	Hyaluronic acid	VAS WOMAC RoM X-Ray knee joint space width WORMS	12 mo
Turajane (2017) ⁹³ Turajane T. Chaveewanakorn U. Fongsarun W. Aojanepong J. Papadopoulos K.I. 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 Cell Int. 2017; 2017: 8925132 PubMed Google Scholar	Thailand	I	40 (13/27)	Knee	PBSC	Hyaluronic acid, GFA (PRP, hG-CSF)	Need for surgical intervention at 12mo WOMAC	12 mo
Vega (2015) ⁹⁴ Vega A. Martin-Ferrero M.A. Del Canto F. Alberca M. Garcia V. Munar A. et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation. 2015 Aug; 99: 1681-1690 Crossref PubMed Scopus (383) Google Scholar	Spain	I	15 (6/9)	Knee	Allogeneic culture-expanded BMSC	n/a	VAS WOMAC Lequesne functional index SF-12 life quality questionnaire MRI T2 mapping, PCI	12 mo
Centeno (2014) ⁸⁸ Centeno C.J. Freeman M.D. Percutaneous injection of autologous, culture-expanded mesenchymal stem cells into carpometacarpal hand joints: a case series with an untreated comparison group. Wien Med Wochenschr (1946). 2014 Mar; 164: 83-87 Crossref PubMed Scopus (21) Google Scholar	Denmark, Sweden, USA	II	6 (4/2)	Hand	Culture-expanded BMSC	Platelet lysate	Percent pain relief Modified VAS Strength, ROM	12 mo
Jo (2014) ¹³ Jo C.H. Lee Y.G. Shin W.H. Kim H. Chai J.W. Jeong E.C. et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem cell (Dayton, Ohio). 2014 May; 32: 1254-1266 Crossref PubMed Scopus (597) Google Scholar	Korea	II	18 (3/15)	Knee	Culture-expanded ADSC	n/a	WOMAC Safety Secondary: VAS, KSS, radiographic, histologic evaluation	6 mo
Jo (2017) ⁹⁰ Jo C.H. Chai J.W. Jeong E.C. Oh S. Shin J.S. Shim H. et al. 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 Oct; 45: 2774-2783 Crossref PubMed Scopus (130) Google Scholar	Korea	II	18 (3/15)	Knee	Culture-expanded ADSC	n/a	WOMAC KSS KOOS VAS for pain MRI evaluation including cartilage defect size	24 mo Follow-up Jo (2014) ¹⁴ Diekman B.O. Guilak F. Stem cell-based therapies for osteoarthritis: challenges and opportunities. Curr Opin Rheumatol. 2013 Jan; 25: 119-126 Crossref PubMed Scopus (101) Google Scholar
Koh (2014) ⁹¹ Koh Y.G. Kwon O.R. Kim Y.S. Choi Y.J. 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: J Arthroscopic Relat Dis: Off Pub Arthroscopy Assoc North America Int Arthroscopy Assoc. 2014 Nov; 30: 1453-1460 Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar	Korea	II	21 (5/16)	Knee	SVF/ADSC	PRP	KOOS Lysholm score X-Ray (femorotibial angle, weight-bearing line) Second-look arthroscopy evaluation of cartilage – Kanamiya grading system	Mean 24.2 ± 4.7 mo
Nguyen (2016) ³⁰ Nguyen P.D. Tran T.D. Nguyen H.T. Vu H.T. Le P.T. Phan N.L. et al. Comparative clinical observation of arthroscopic microfracture in the presence and absence of a stromal vascular fraction injection for osteoarthritis. Stem Cells Transl Med. 2017 Jan; 6: 187-195 Crossref PubMed Scopus (62) Google Scholar	Vietnam	II	15 (3/12)	Knee	SVF/ADSC	PRP	WOMAC Lysolm score VAS for pain Modified Outerbridge classification	18 mo
Pers (2016) ⁹⁷ Pers Y.M. Rackwitz L. Ferreira R. Pullig O. Delfour C. Barry F. et al. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial. Stem Cells Transl Med. 2016 Jul; 5: 847-856 Crossref PubMed Scopus (317) Google Scholar	France, Germany	II	18 (8/10)	Knee	Culture-expanded ADSC	n/a	VAS for pain WOMAC Patient Global Assessment KOOS SAS SF-36 OARSI/OMERACT Responders	6 mo
Shapiro (2017) ⁹² Shapiro S.A. Kazmerchak S.E. Heckman M.G. Zubair A.C. O'Connor M.I. A prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis. Am J Sports Med. 2017 Jan; 45: 82-90 Crossref PubMed Scopus (168) Google Scholar	USA	II	25 (7/18)	Knee	BMAC/BMSC	Platelet-poor bone marrow plasma	VAS for pain ICOAP WOMAC KOOS Activity level	6 mo
Wakitani (2002) ⁹⁵ Wakitani S. Imoto K. Yamamoto T. Saito M. Murata N. Yoneda M. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthritis Cartilage/OARS, Osteoarthritis Res Soc. 2002 Mar; 10: 199-206 Abstract Full Text PDF PubMed Scopus (795) Google Scholar	Japan	II	12 (X/X)	Knee	Culture-expanded BMSC	Collagen gel sheet	Hospital for Special Surgery Knee Rating Scale Arthroscopic and Histologic cartilage evaluation	Mean: 16 months
Wong (2013) ⁹⁶ Wong K.L. Lee K.B. Tai B.C. Law P. Lee E.H. Hui J.H. 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: J Arthroscopic Relat Sur: Off Pub Arthroscopy Assoc North America Int Arthroscopy Assoc. 2013 Dec; 29: 2020-2028 Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar	Singapore	II	28 (15/13)	Knee	Culture-expanded BMSC	Hyaluronic acid	Tegner activity score Lysholm score IKDC ICRS MOCART	2 yrs
Centeno (2015) ⁴⁶ Centeno C. Pitts J. Al-Sayegh H. Freeman M. Efficacy of autologous bone marrow concentrate for knee osteoarthritis with and without adipose graft. BioMed Res Int. 2014; 2014: 370621 Crossref PubMed Scopus (115) Google Scholar	USA	III	373 (283/126)	Knee	BMAC/BMSC	PRP, Platelet lysate	NPS LEFS Subjective Improvement Rating Scale IKDC	Varied by outcome, at least 12 mo
Centeno (2014) ⁴⁴ Bansal H. Comella K. Leon J. Verma P. Agrawal D. Koka P. et al. Intra-articular injection in the knee of adipose derived stromal cells (stromal vascular fraction) and platelet rich plasma for osteoarthritis. J Transl Med. 2017; 15 (no pagination)(141) Crossref PubMed Scopus (83) Google Scholar	USA	III	681 (516/324) ^† Based on number of knees treated.	Knee	BMAC/BMSC ± SVF/ADSC	PRP, Platelet lysate	NPS LEFS Subjective Improvement Rating Scale	12 mo
Kim (2015) ⁶⁰ Kim Y.S. Choi Y.J. Suh D.S. Heo D.B. Kim Y.I. Ryu J.-S. et al. Mesenchymal stem cell implantation in osteoarthritic knees: is fibrin glue effective as a scaffold?. Am J Sports Med. 2015; 43: 176-185 Crossref PubMed Scopus (117) Google Scholar	Korea	III	56 (22/32) ^† Based on number of knees treated.	Knee	SVF/ADSC	Group 1: n/a Group 2: fibrin glue product	IKDC Tegner activity scale ICRS grade	Mean 28.6 ± 3.9 mo (Range 24–34 mo)
Kim (2016) ⁶¹ Kim Y.S. Koh Y.G. Injection of mesenchymal stem cells as a supplementary Strategy of marrow stimulation improves cartilage regeneration after lateral sliding calcaneal osteotomy for varus ankle osteoarthritis: clinical and second-look arthroscopic results. Arthrosc J Arthrosc Relat Surg. 2016; 32: 878-889 Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar	Korea	III	26 (11/15)	Ankle	SVF/ADSC	n/a	VAS for pain AOFAS Radiological talar tilt angle ICRS grade	Mean 27.7 ± 2.4 mo (Range 24–34 mo)
Kim (2015) ⁶² Kim Y.S. Kwon O.R. Choi Y.J. Suh D.S. Heo D.B. Koh Y.G. Comparative matched-pair analysis of the injection versus implantation of mesenchymal stem cells for knee osteoarthritis. Am J Sports Med. 2015; 43: 2738-2746 Crossref PubMed Scopus (81) Google Scholar	Korea	III	40 (14/26)	Knee	SVF/ADSC	Injection group: PRP Implantation group: Fibrin glue product	IKDC Tegner activity scale ICRS grade	Injection group: 28.5 ± 4.8 mo Implantation group: 28.8 ± 4.0 mo
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Koh (2012) ⁹¹ Koh Y.G. Kwon O.R. Kim Y.S. Choi Y.J. 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: J Arthroscopic Relat Dis: Off Pub Arthroscopy Assoc North America Int Arthroscopy Assoc. 2014 Nov; 30: 1453-1460 Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar	Korea	III	25 (8/17)	Knee	SVF/ADSC	PRP	Lysholm score Tegner activity scale VAS for pain	Mean 16.4 ± 2.3 mo (Range 12–18 mo)
Ahmad (2014) ⁴³ Ahmad K.A. Ibrahim Y.A. Saber N.Z. Darwish B.A. MR cartilage imaging in assessment of the regenerative power of autologous peripheral blood stem cell injection in knee osteoarthritis. Egypt J Radiol Nucl Med. 2014 September; 45: 787-794 Abstract Full Text Full Text PDF Scopus (7) Google Scholar	Egypt	IV	10 (3/7)	Knee	PBSC	n/a	WOMAC 6MWD MOAKS	12 mo
Bansal (2017) ⁴⁴ Bansal H. Comella K. Leon J. Verma P. Agrawal D. Koka P. et al. Intra-articular injection in the knee of adipose derived stromal cells (stromal vascular fraction) and platelet rich plasma for osteoarthritis. J Transl Med. 2017; 15 (no pagination)(141) Crossref PubMed Scopus (83) Google Scholar	India	IV	10 (6/4)	Knee	SVF/ADSC	PRP	WOMAC 6MWD X-Ray joint space width MRI articular cartilage thickness	2 yrs
Buda (2016) ⁴⁵ Buda R. Castagnini F. Cavallo M. Ramponi L. Vannini F. Giannini S. One-step" bone marrow-derived cells transplantation and joint debridement for osteochondral lesions of the talus in ankle osteoarthritis: clinical and radiological outcomes at 36 months. Arch Orthop Trauma Surg. 2016; 136: 107-116 Crossref PubMed Scopus (24) Google Scholar	Italy	IV	56 (37/19)	Ankle	BMAC/ BMSC	Autologous platelet-rich fibrin	AOFAS MOCART	36 mo
Centeno (2011) ⁵² Centeno C.J. Schultz J.R. Cheever M. Freeman M. Faulkner S. Robinson B. et al. Safety and complications reporting update on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther. 2011 Dec; 6: 368-378 Crossref PubMed Scopus (110) Google Scholar	USA	IV	135 (93/42)	Knee	Culture-expanded BMSC	Platelet lysate or PRP	Likert scale for reported pain relief	Mean 11.3 mo
Centeno (2015) ⁴⁷ Centeno C.J. Al-Sayegh H. Bashir J. Goodyear S. Freeman M.D. 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: 269-276 PubMed Google Scholar	USA	IV	34 (27/7)	Shoulder	BMAC/BMSC	PRP, Platelet lysate	DASH NPS Subjective Improvement Rating Scale	At least 3 mo
Davatchi (2011) ⁵³ Davatchi F. Abdollahi B.S. Mohyeddin M. Shahram F. Nikbin B. Mesenchymal stem cell therapy for knee osteoarthritis. Preliminary report of four patients. Int J Rheum Dis. 2011; 14: 211-215 Crossref PubMed Scopus (290) Google Scholar	Iran	IV	4 (2/2)	Knee	Culture-expanded BMSC	Physiological serum	VAS for pain Walking time to pain Number of stairs to pain Time to gelling pain RoM Patellar crepitus Swelling, Instability	6 mo
Davatchi (2016) ⁵⁴ Davatchi F. Sadeghi Abdollahi B. Mohyeddin M. Nikbin B. Mesenchymal stem cell therapy for knee osteoarthritis: 5 years follow-up of three patients. Int J Rheum Dis. 2016; 19: 219-225 Crossref PubMed Scopus (129) Google Scholar	Iran	IV	4 (2/2)	Knee	Culture-expanded BMSC	Physiological serum	Same as Davatchi (2011) ⁷ Nelson A.E. Allen K.D. Golightly Y.M. Goode A.P. Jordan J.M. A systematic review of recommendations and guidelines for the management of osteoarthritis: the chronic osteoarthritis management initiative of the U.S. bone and joint initiative. Semin Arthritis Rheum. 2014 Jun; 43: 701-712 Crossref PubMed Scopus (505) Google Scholar Patient Global Assessment	5 yrs Follow-up Davatchi (2011) ⁷ Nelson A.E. Allen K.D. Golightly Y.M. Goode A.P. Jordan J.M. A systematic review of recommendations and guidelines for the management of osteoarthritis: the chronic osteoarthritis management initiative of the U.S. bone and joint initiative. Semin Arthritis Rheum. 2014 Jun; 43: 701-712 Crossref PubMed Scopus (505) Google Scholar
Emadedin (2012) ²³ Emadedin M. Aghdami N. Taghiyar L. Fazeli R. Moghadasali R. Jahangir S. et al. Intra-articular injection of autologous mesenchymal stem cells in six patients with knee osteoarthritis. Arch Iran Med. 2012 Jul; 15: 422-428 PubMed Google Scholar	Iran	IV	6 (0/6)	Knee	Culture-expanded BMSC	n/a	VAS WOMAC Walking distance Time to gelling Patellar crepitus RoM MRI cartilage assessment	12 mo
Emadedin (2015) ⁵⁵ Emadedin M. Ghorbani Liastani M. Fazeli R. Mohseni F. Moghadasali R. Mardpour S. et al. Long-term follow-up of intra-articular injection of autologous mesenchymal stem cells in patients with knee, Ankle, or Hip Osteoarthritis. Arch Iran Med. 2015; 18: 336-344 PubMed Google Scholar	Iran	IV	17(X/X)	Ankle (n = 6) Hip (n = 5) Knee (n = 6)	Culture-expanded BMSC	n/a	VAS WOMAC HHS FAOS Walking distance Lab studies MRI analysis	30 mo
Fodor (2016) ⁵⁶ Fodor P.B. Paulseth S.G. Adipose derived stromal cell (ADSC) injections for pain management of osteoarthritis in the human knee joint. Aesthetic Surg J. 2016 Feb; 36: 229-236 Crossref PubMed Scopus (95) Google Scholar	USA	IV	6 (1/7) ^† Based on number of knees treated.	Knee	SVF/ADSC	n/a	VAS for pain WOMAC RoM Timed up-and-go MRI - observational	1 yr
Gibbs (2015) ⁵⁷ Gibbs N. Diamond R. Sekyere E.O. Thomas W.D. Management of knee osteoarthritis by combined stromal vascular fraction cell therapy, platelet-rich plasma, and musculoskeletal exercises: a case series. J Pain Res. 2015; 8: 799-806 Crossref PubMed Scopus (58) Google Scholar	Australia	IV	4 (2/2)	Knee	SVF/ADSC	PRP, Moderate exercise program	KOOS Physical function tests: GUG, SCT RPE	12 mo
Hudetz (2017) ⁵⁸ Hudetz D. Boric I. Rod E. Jelec Z. Radic A. Vrdoljak T. et al. The effect of intra-articular injection of autologous microfragmented fat tissue on proteoglycan synthesis in patients with knee osteoarthritis. Genes (Basel). 2017; 8 Crossref PubMed Scopus (70) Google Scholar	Croatia	IV	17 (12/5)	Knee	Microfragmented/ADSC	n/a	VAS for pain dGEMRIC IgG Glycans	12 mo
Kim (2015) ²⁶ Kim Y.S. Choi Y.J. Koh Y.G. Mesenchymal stem cell implantation in knee osteoarthritis: an assessment of the factors influencing clinical outcomes. Am J Sports Med. 2015 Sep; 43: 2293-2301 Crossref PubMed Scopus (74) Google Scholar	Korea	IV	49 (26/29) ^† Based on number of knees treated.	Knee	SVF/ADSC	Fibrin glue product	IKDC score Tegner activity scale Overall surgery satisfaction	Mean 26.7 ± 3.6 mo (Range 24–36 mo)
Kim (2016) ⁵⁹ Kim Y.S. Choi Y.J. Lee S.W. Kwon O.R. Suh D.S. Heo D.B. et al. 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 Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar	Korea	IV	20 (9/15) ^† Based on number of knees treated.	Knee	SVF/ADSC	Fibrin glue product	IKDC Tegner activity scale MOAKS MOCART	Mean 27.9 ± 3.2 mo (Range 24–34 mo)
Koh (2015) ⁶⁴ Koh Y.-G. Choi Y.-J. Kwon S.-K. Kim Y.-S. Yeo J.-E. Clinical results and second-look arthroscopic findings after treatment with adipose-derived stem cells for knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2015; 23: 1308-1316 Crossref PubMed Scopus (175) Google Scholar	Korea	IV	30 (5/25)	Knee	SVF/ADSC	PRP	KOOS Lysholm score VAS Second-look arthroscopy evaluation of cartilage	24 mo
Koh (2013) ⁶⁵ Koh Y.-G. Jo S.-B. Kwon O.-R. Suh D.-S. Lee S.-W. Park S.-H. et al. Mesenchymal stem cell injections improve symptoms of knee osteoarthritis. Arthroscopy: J Arthroscopy Relat Dis. 2013; 29: 748-755 Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar	Korea	IV	18 (6/12)	Knee	SVF/ADSC	PRP	WOMAC Lysholm score VAS for pain WORMS	Mean 24.3 ± 0.8 mo (Range 24–26 mo)
Koh (2014) ⁶⁷ Koh Y.G. Choi Y.J. Kwon O.R. Kim Y.S. Second-look arthroscopic evaluation of cartilage lesions after mesenchymal stem cell implantation in osteoarthritic knees. Am J Sports Med. 2014; 42: 1628-1637 Crossref PubMed Scopus (129) Google Scholar	Korea	IV	56 (22/34)	Knee	SVF/ADSC	n/a	IKDC Tegner activity scale Patient satisfaction Second-look arthroscopy – ICRS	Mean 26.7 ± 2.5 mo
Mardones (2017) ⁶⁸ Mardones R. Jofre C.M. Tobar L. Minguell J.J. Mesenchymal stem cell therapy in the treatment of hip osteoarthritis. J Hip Preserv Surg. 2017; 4: 159-163 Crossref PubMed Google Scholar	Chile	IV	10 (7/6) ^† Based on number of knees treated.	Hip	Culture-expanded BMSC	n/a	VAS WOMAC HHS VAIL hip score Tönnis Classification of Osteoarthritis	Range 16–40 mo
Murphy (2017) ⁷⁰ Murphy M.P. Buckley C. Sugrue C. Carr E. O'Reilly A. O'Neill S. et al. ASCOT: autologous bone marrow stem cell use for osteoarthritis of the thumb-first carpometacarpal joint. Plast Reconstr Surg Glob Open. 2017; 5: e1486 Crossref PubMed Scopus (7) Google Scholar	Ireland	IV	13 (2/11)	Thumb – CMC joint	BMAC/BMSC	Tisseel	VAS RoM Kapandji opposition score Strength (pinch test) DASH Grind test	12 mo
Oliver (2014) ⁸⁶ Oliver K. Bayes M. Crane D. Pathikonda C. Clinical outcome of bone marrow concentrate in knee osteoarthritis. J Prolotherapy. 2015; 7: 937-946 Google Scholar	USA	IV	70 (21/49), 122 knees	Knee	BMAC/BMSC + SVF/ADSC	n/a	KOOS Adverse events	180 days
Orozco (2013) ⁷¹ Orozco L. Munar A. Soler R. Alberca M. Soler F. Huguet M. et al. Treatment of knee osteoarthritis with autologous mesenchymal stem cells: a pilot study. Transplantation. 2013 Jun 27; 95: 1535-1541 Crossref PubMed Scopus (325) Google Scholar	Spain	IV	12 (6/6)	Knee	Culture-expanded BMSC	n/a	VAS WOMAC Lequesne severity index SF-36 Quality of Life Questionnnaire Poor Cartilage Index – MRI	12 mo
Orozco (2014) ⁷² Orozco L. Munar A. Soler R. Alberca M. Soler F. Huguet M. et al. Treatment of knee osteoarthritis with autologous mesenchymal stem cells: two-year follow-up results. Transplantation. 2014; 97: e66-e68 Crossref PubMed Scopus (119) Google Scholar	Spain	IV	12 (6/6)	Knee	Culture-expanded BMSC	n/a	VAS WOMAC Lequesne severity index Poor Cartilage Index – MRI	2 yrs Follow-up Orozco (2013) ³¹ Sakaguchi Y. Sekiya I. Yagishita K. Muneta T. Comparison of human stem cells derived from various mesenchymal tissues: superiority of synovium as a cell source. Arthritis Rheum. 2005 Aug; 52: 2521-2529 Crossref PubMed Scopus (1224) Google Scholar
Pak (2011) ⁹⁴ Vega A. Martin-Ferrero M.A. Del Canto F. Alberca M. Garcia V. Munar A. et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation. 2015 Aug; 99: 1681-1690 Crossref PubMed Scopus (383) Google Scholar	Korea	IV	2 (0/2)	Knee	SVF/ADSC	PRP, dexamethasone, hyaluronic acid	VAS Functional rating index RoM MRI evaluation of cartilage	3 mo
Pak (2013) ⁷³ Pak J. Regeneration of human bones in hip osteonecrosis and human cartilage in knee osteoarthritis with autologous adipose-tissue-derived stem cells: a case series. J Med Case Rep. 2011; 5 (no pagination)(296) Crossref PubMed Scopus (180) Google Scholar	Korea	IV	74 (X/X)	Hip (n = 7) Ankle (n = 2) Knee (n = 74)	SVF/ADSC	PRP, Hyaluronic acid	VAS for pain MRI – assessed for tumor formation	At least 12 mo
Pak (2016) ⁷⁴ Pak J. Chang J.J. Lee J.H. Lee S.H. Safety reporting on implantation of autologous adipose tissue-derived stem cells with platelet-rich plasma into human articular joints. BMC Muscoskel Disord. 2013 Dec 1; 14: 337 Crossref PubMed Scopus (117) Google Scholar	Korea	IV	3 (1/2)	Knee	SVF/ADSC	ECM, Hyaluronic acid, PRP	VAS Functional rating Index RoM MRI cartilage assessment	18 wks
Park (2017) ⁷⁵ Pak J. Lee J.H. Park K.S. Jeong B.C. Lee S.H. Regeneration of cartilage in human knee osteoarthritis with autologous adipose tissue-derived stem cells and autologous extracellular matrix. BioResearch Open Access. 2016; 5: 192-200 Crossref PubMed Scopus (48) Google Scholar	Korea	IV	7 (2/5)	Knee	Allogeneic, culture-expanded hUCB-MSCs	Hyaluronic acid hydrogel	ICRS grade VAS for pain IKDC Histological findings	7 yrs
Pintat (2017) ⁷⁸ Pintat J. Silvestre A. Magalon G. Gadeau A.P. Pesquer L. Perozziello A. et al. Intra-articular injection of mesenchymal stem cells and platelet-rich plasma to treat patellofemoral osteoarthritis: preliminary results of a long-term pilot study. J Vasc Intervent Radiol. 2017; 28: 1708-1713 Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar	France	IV	19 (10/9)	Patellofemoral	SVF/ADSC	PRP	WOMAC MRI – ICRS-like classification	12 mo
Russo (2017) ⁷⁹ Russo A. Condello V. Madonna V. Guerriero M. Zorzi C. Autologous and micro-fragmented adipose tissue for the treatment of diffuse degenerative knee osteoarthritis. J Exp Orthop. 2017; 4 (no pagination)(33) Crossref Scopus (55) Google Scholar	Italy	IV	30 (21/9)	Knee	Microfragmented/ADSC	n/a	VAS for pain KOOS IKDC - subjective Tegner Lysholm Knee	12 mo
Soler (2016) ⁸⁰ Soler R. Orozco L. Munar A. Huguet M. Lopez R. Vives J. et al. Final results of a phase I-II trial using ex vivo expanded autologous Mesenchymal Stromal Cells for the treatment of osteoarthritis of the knee confirming safety and suggesting cartilage regeneration. Knee. 2016; 23: 647-654 Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar	Spain	IV	15 (6/9)	Knee	Culture-expanded BMSC	n/a	VAS for pain WOMAC HAQ, pain subscale SF-36 Lequesne functional index MRI T2 mapping	12 mo
Turajane (2013) ³² Turajane T. Chaweewannakorn U. Larbpaiboonpong V. Aojanepong J. Thitiset T. Honsawek S. et al. Combination of intra-articular autologous activated peripheral blood stem cells with growth factor addition/preservation and hyaluronic acid in conjunction with arthroscopic microdrilling mesenchymal cell stimulation Improves quality of life and regenerates articular cartilage in early osteoarthritic knee disease. J Med Assoc Thail = Chot Thangphaet. 2013 May; 96: 580-588 PubMed Google Scholar	Thailand	IV	5 (1/4)	Knee	PBSC	Hyaluronic acid, GFA (PRP, hG-CSF)	WOMAC KOOS	6 mo
Bui (2014) ⁸⁵ Bui K. Duong T. Nguyen N. Nguyen T. Le V. Mai V. et al. Symptomatic knee osteoarthritis treatment using autologous adipose derived stem cells and platelet rich plasma: a clinical study. Biomed Res Ther. 2014; 1: 2-8 Crossref Google Scholar	Vietnam	IV	21 (X/X)	Knee	SVF/ADSC	PRP	VAS for pain Lysholm score MRI cartilage assessment	8.5 mo
Varma (2010) ⁸¹ Varma H.S. Dadarya B. Vidyarthi A. The new avenues in the management of osteo-arthritis of knee - stem cells. J Indian Med Assoc. 2010; 108: 583-585 PubMed Google Scholar	India	IV	50 (X/X)	Knee	BMAC/BMSC	n/a	VAS OAOS	6 mo
Wakitani (2011) ⁸² Wakitani S. Okabe T. Horibe S. Mitsuoka T. Saito M. Koyama T. et al. Safety of autologous bone marrow-derived mesenchymal stem cell transplantation for cartilage repair in 41 patients with 45 joints followed for up to 11 years and 5 months. J Regen Med Tissue Eng. 2011 Feb; 5: 146-150 Crossref Scopus (253) Google Scholar	Japan	IV	26 (X/X)	Knee	Culture-expanded BMSC	Collagen gel sheet	Adverse events: tumor development and infection	Mean: 75 mo
Wei (2011) ⁸³ Wei N. Beard S. Delauter S. Bitner C. Gillis R. Rau L. et al. Guided mesenchymal stem cell layering technique for treatment of osteoarthritis of the knee. J Appl Res Clin Exp Therapeut. 2011; 11: 44-48 Google Scholar	USA	IV	23 (17/6)	Knee	BMAC/BMSC	PRP	WOMAC VAS for pain Patient Global Assessment 50 foot walk pain Physician Global Assessment	12 mo
Yokota (2017) ⁸⁴ Yokota N. Yamakawa M. Shirata T. Kimura T. Kaneshima H. Clinical results following intra-articular injection of adipose-derived stromal vascular fraction cells in patients with osteoarthritis of the knee. Regen Ther. 2017; 6: 108-112 Crossref PubMed Scopus (49) Google Scholar	Japan	IV	13 (4/22) ^† Based on number of knees treated.	Knee	SVF/ADSC	n/a	VAS for pain JKOM WOMAC	6 mo
Centeno (2008) ⁴⁹ Centeno C.J. Busse D. Kisiday J. Keohan C. Freeman M. Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells, platelet lysate and dexamethasone. Am J Case Rep. 2008; 9: 246-251 Google Scholar	USA	V	1(0/1)	Knee	Culture-expanded BMSC	Autologous whole-marrow, platelet lysate, dexamethasone	Modified VAS Functional Rating Index ROM MRI quantitative volume analysis	3 mo
Centeno (2008) ⁵⁰ Centeno C.J. Busse D. Kisiday J. Keohan C. Freeman M. Karli D. Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells. Med Hypotheses. 2008; 71: 900-908 Crossref PubMed Scopus (109) Google Scholar	USA	V	1(1/0)	Knee	Culture- expanded BMSC	Hyoluronate sodium, autologous whole-marrow, platelet lysate, dexamethasone	Modified VAS Functional Rating Index ROM MRI quantitative volume analysis	3 mo
Centeno (2008) ⁵¹ Centeno C.J. Busse D. Kisiday J. Keohan C. Freeman M. Karli D. Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells. Pain Physician. 2008 May-Jun; 11: 343-353 PubMed Google Scholar	USA	V	1 (1/0)	Knee	Culture- expanded BMSC	Autologous marrow-derived nucleated cells, platelet lysate, dexamethasone	Modified VAS Functional rating index ROM MRI quantitative volume analysis	6 mo
Mehrabani (2016) ⁶⁹ Mehrabani D. Mojtahed Jaberi F. Zakerinia M. Hadianfard M.J. Jalli R. Tanideh N. et al. The healing effect of bone marrow-derived stem cells in knee osteoarthritis: a case report. World J Plast Surg. 2016; 5: 168-174 PubMed Google Scholar	Iran	V	1 (0/1)	Knee	Culture-expanded BMSC	n/a	WOMAC VAS for pain Walking distance Time to gelling Patellar crepitus RoM MRI cartilage assessment	12mo
Pak (2017) ⁹⁷ Pers Y.M. Rackwitz L. Ferreira R. Pullig O. Delfour C. Barry F. et al. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial. Stem Cells Transl Med. 2016 Jul; 5: 847-856 Crossref PubMed Scopus (317) Google Scholar	Korea	V	1 (0/1)	Hip	SVF/ADSC	ECM, Hyaluronic acid, PRP	VAS for pain Functional rating index RoM MRI assessment of cartilage	20 wks

ADSC = adipose-derived stem cell; BMSC = bone-marrow stem cell; MSC = mesenchymal stem cell; OA = osteoarthritis; PBSC = peripheral blood stem cell; BMAC = bone marrow aspirate stem cell concentrate.

WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index; MOAKS = MRI Osteoarthritis Knee Score; AOFAS = American Orthopedic Foot and Ankle Score; VAS = Visual Analogue Scale; ROM = Range of Motion; HHS = Harris Hip Score; FAOS = Foot and Ankle Outcome Score; ICOAP = intermittent and constant osteoarthritis pain; WORMS = Whole-Organ Magnetic Resonance Imaging Score; KSS = Knee Society Clinical Rating System; KOOS = Knee Injury and Osteoarthritis Outcome Score; IKDC = International Knee Documentation Committee; MOCART = Magnetic Resonance Observation of Cartilage Repair Tissue; ICRS = International Cartilage Repair Society; CMC = carpometacarpal; DASH = Disability of the Arm, Shoulder, and Hand scoring system; hUCB-MSCs = human umbilical cord blood-derived mesenchymal stem cells; SAS = Short Arthritis Assessment Scale; OARSI/OMERACT = Osteoarthritis Research Society International/Outcome Measures in Rheumatology response defined as 20% improvement of VAS and WOMAC from baseline; HAQ = Health Assessment Questionnaire; OAOS = Osteoarthritis Outcome Score; G-CSF = granulocyte colony stimulating factor; SVF = stromal vascular fraction; PRP = platelet-rich plasma; GFA = Growth Factor Addition; NPS = Numeric Pain Scale; GUG = Get-u and Go test; SCT = Stair Climbing Test; RPE = Rate of Perceived Exertion; dGEMRIC = delayed gadolinium-enhanced magnetic resonance imaging of cartilage; ECM = extracellular matrix; JKOM = Japanese Knee Osteoarthritis Measure; LEFS = Lower Extremity Functional Scale.

∗ N = number of patients in the treatment group.

† Based on number of knees treated.

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In the 61 clinical studies, MSC type varied between ADSCs (29 studies), BMSCs (30 studies), and PBSCs (3 studies), and allogeneic umbilical cord-derived MSCs (1 study), taking into account that two studies used both ADSCs and BMSCs

⁶²

Kim Y.S.
Kwon O.R.
Choi Y.J.
Suh D.S.
Heo D.B.
Koh Y.G.

Comparative matched-pair analysis of the injection versus implantation of mesenchymal stem cells for knee osteoarthritis.

^,

⁸⁶

Oliver K.
Bayes M.
Crane D.
Pathikonda C.

Clinical outcome of bone marrow concentrate in knee osteoarthritis.

Google Scholar

. Among these studies, the processing and injected/implanted form also differed. ADSCs were either culture-expanded (n = 3), within SVF (n = 24) or microfragmented adipose tissue (n = 2). BMSCs were either culture-expanded (n = 18), within BMAC (n = 10), or allogenic (n = 2). Three studies used PBSCs and one study used allogeneic umbilical cord-derived MSCs. Several adjuvants were injected/implanted with the MSCs, including PRP (n = 20), platelet lysate (n = 8), and hyaluronic acid (n = 10). The median follow-up time was 12 months with a range of 3–84 months.

To better understand the quality of the literature pertaining to MSCs as OA therapy, the fourteen Level I and Level II articles were analyzed further.

Levels I–II only: study characteristics

Of the fourteen Level I and Level II evidence articles, 288 total patients were studied. Sixty-three percent of these patients were female (n = 181). Thirteen studies treated knee OA and 1 treated hand OA. Study characteristics of the Level I and II studies can be found in Table II. As depicted in Table III, the RoB 2.0 and ROBINS-I risk of bias quality assessment yielded five studies at low risk of bias, seven at moderate/some concerns risk, and two at high risk.

Table IIIRisk of Bias assessment using Cochrane's RoB 2.0 Scale for level I evidence studies and ROBINS-I scale for level II evidence studies

First Author (Date of publication)	Risk due to
First Author (Date of publication)	Randomized process	Confounding	Participant selection	Intervention classification	Deviations from intended intervention	Missing data	Outcomes measurement	Selection of reported result	Overall
Garay-Mendoza (2017) ²⁹ Garay-Mendoza D. Villarreal-Martinez L. Garza-Bedolla A. Perez-Garza D.M. Acosta-Olivo C. Vilchez-Cavazos F. et al. The effect of intra-articular injection of autologous bone marrow stem cells on pain and knee function in patients with osteoarthritis. Int J Rheum Dis. 2017 Jul 27; 21: 140-147 Crossref PubMed Scopus (49) Google Scholar	Low				Low	Low	Low	Low	Low
Gupta (2016) ⁸⁹ Gupta P.K. Chullikana A. Rengasamy M. Shetty N. Pandey V. Agarwal V. et al. Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel(R)): preclinical and clinical trial in osteoarthritis of the knee joint. Arthritis Res Ther. 2016 Dec 20; 18: 301 Crossref PubMed Scopus (181) Google Scholar	Low				Low	Low	Low	Low	Low
Lamo-Espinosa (2016) ⁸⁷ Lamo-Espinosa J.M. Mora G. Blanco J.F. Granero-Molto F. Nunez-Cordoba J.M. Sanchez-Echenique C. et al. Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II). J Transl Med. 2016 Aug 26; 14: 246 Crossref PubMed Scopus (184) Google Scholar	Low				Low	Low	Low	Low	Low
Turajane (2017) ⁹³ Turajane T. Chaveewanakorn U. Fongsarun W. Aojanepong J. Papadopoulos K.I. 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 Cell Int. 2017; 2017: 8925132 PubMed Google Scholar	Low				Low	Low	Low	Low	Low
Vega (2015) ⁹⁴ Vega A. Martin-Ferrero M.A. Del Canto F. Alberca M. Garcia V. Munar A. et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation. 2015 Aug; 99: 1681-1690 Crossref PubMed Scopus (383) Google Scholar	Low				Low	Low	Low	Low	Low
Centeno (2014) ⁸⁸ Centeno C.J. Freeman M.D. Percutaneous injection of autologous, culture-expanded mesenchymal stem cells into carpometacarpal hand joints: a case series with an untreated comparison group. Wien Med Wochenschr (1946). 2014 Mar; 164: 83-87 Crossref PubMed Scopus (21) Google Scholar		Moderate	Low	Low	Low	Moderate	Moderate	Low	Moderate
Jo (2014) ¹³ Jo C.H. Lee Y.G. Shin W.H. Kim H. Chai J.W. Jeong E.C. et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem cell (Dayton, Ohio). 2014 May; 32: 1254-1266 Crossref PubMed Scopus (597) Google Scholar		Moderate	Low	Moderate	Low	Low	Moderate	Low	Moderate
Jo (2017) ⁹⁰ Jo C.H. Chai J.W. Jeong E.C. Oh S. Shin J.S. Shim H. et al. 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 Oct; 45: 2774-2783 Crossref PubMed Scopus (130) Google Scholar		Moderate	Low	Moderate	Low	Moderate	Moderate	Low	Moderate
Koh (2014) ⁹¹ Koh Y.G. Kwon O.R. Kim Y.S. Choi Y.J. 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: J Arthroscopic Relat Dis: Off Pub Arthroscopy Assoc North America Int Arthroscopy Assoc. 2014 Nov; 30: 1453-1460 Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar	Low				Low	Some concerns	Low	Low	Some concerns
Nguyen (2016) ³⁰ Nguyen P.D. Tran T.D. Nguyen H.T. Vu H.T. Le P.T. Phan N.L. et al. Comparative clinical observation of arthroscopic microfracture in the presence and absence of a stromal vascular fraction injection for osteoarthritis. Stem Cells Transl Med. 2017 Jan; 6: 187-195 Crossref PubMed Scopus (62) Google Scholar		Low	Low	Low	Low	Low	Moderate	Moderate	Moderate
Pers (2016) ⁹⁷ Pers Y.M. Rackwitz L. Ferreira R. Pullig O. Delfour C. Barry F. et al. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial. Stem Cells Transl Med. 2016 Jul; 5: 847-856 Crossref PubMed Scopus (317) Google Scholar		Low	Low	Moderate	Moderate	Moderate	Moderate	Low	Moderate
Shapiro (2017) ⁹² Shapiro S.A. Kazmerchak S.E. Heckman M.G. Zubair A.C. O'Connor M.I. A prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis. Am J Sports Med. 2017 Jan; 45: 82-90 Crossref PubMed Scopus (168) Google Scholar	Low				Low	Low	Some concerns	Low	Some concerns
Wakitani (2002) ⁹⁵ Wakitani S. Imoto K. Yamamoto T. Saito M. Murata N. Yoneda M. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthritis Cartilage/OARS, Osteoarthritis Res Soc. 2002 Mar; 10: 199-206 Abstract Full Text PDF PubMed Scopus (795) Google Scholar	Some concerns				Low	Some concerns	Some concerns	Some concerns	High
Wong (2013) ⁹⁶ Wong K.L. Lee K.B. Tai B.C. Law P. Lee E.H. Hui J.H. 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: J Arthroscopic Relat Sur: Off Pub Arthroscopy Assoc North America Int Arthroscopy Assoc. 2013 Dec; 29: 2020-2028 Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar	Some concerns				Low	Low	Some concerns	Some concerns	High

NI = no information

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Levels I–II only: intervention details

In the Levels I and II cohort, 288 patients received MSC therapy. MSC regimen varied; a summary of the intervention details can be found in Table IV. Eight studies used BMSCs collected from the iliac crest. Of these, four were culture-expanded, 2 were BMAC and 2 were allogeneic. Five studies used ADSCs with four derived from abdominal fat and one from the buttocks. Of these five studies, 3 were culture-expanded injecting a range of 2 × 10⁶ to 100 × 10⁶ ADSCs and 2 were from SVF injecting a magnitude of 10⁷ SVF cells with one study estimating this as 4.11 × 10⁶ ADSCs

⁸⁵

Bui K.
Duong T.
Nguyen N.
Nguyen T.
Le V.
Mai V.
et al.

Symptomatic knee osteoarthritis treatment using autologous adipose derived stem cells and platelet rich plasma: a clinical study.

. Turajane, Chaveewanakown, Fongsarun, Aojanepong and Papadopoulos (2017) was the only one of these studies to inject 3 ml PBSCs containing a range of 1.095–1.276 × 10⁶ total nucleated cells. This study employed three injections and compared groups that received microdriling, PBSC, growth factor addition, and HA (group 1) vs PBSC, PRP, HA (group 2) vs HA alone (group 3). The mean follow-up length of time for all studies was 14 ± 7 mo (Range 6 to 24)

⁹³

Turajane T.
Chaveewanakorn U.
Fongsarun W.
Aojanepong J.
Papadopoulos K.I.

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.

.

Table IVIntervention details of the included level I and II evidence studies

First Author (Date of publication)	MSC type & extraction site	Biologic adjuvant	Injection procedure	Number of injected MSCs	Follow-up	Number of injections
Garay-Mendoza (2017) ²⁹ Garay-Mendoza D. Villarreal-Martinez L. Garza-Bedolla A. Perez-Garza D.M. Acosta-Olivo C. Vilchez-Cavazos F. et al. The effect of intra-articular injection of autologous bone marrow stem cells on pain and knee function in patients with osteoarthritis. Int J Rheum Dis. 2017 Jul 27; 21: 140-147 Crossref PubMed Scopus (49) Google Scholar	BMAC/BMSC: iliac crest	Outpatient SQ G-CSF x 3 days	Intra-articular injection of 10 mL concentrate without radiographic guidance	10 ml concentrate TNC: 302.2 × 10⁷ Mononuclear: 67.33 × 10⁷ CD34⁺: 20.56 × 10⁶	1 wk, 1, 6 mo	1
Gupta (2016) ⁸⁹ Gupta P.K. Chullikana A. Rengasamy M. Shetty N. Pandey V. Agarwal V. et al. Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel(R)): preclinical and clinical trial in osteoarthritis of the knee joint. Arthritis Res Ther. 2016 Dec 20; 18: 301 Crossref PubMed Scopus (181) Google Scholar	Allogeneic CE BMSC: from 3 healthy volunteers	PLASMALYTE-A Pre: Hydrocortisone and pheniramine maleate Post: Hyaluronic acid	Pre-medication of hydrocortisone and pheniramine maleate. Intra-articular injection without radiographic guidance followed by HA	4 dose levels: 25, 50, 75, 150 × 10⁶	12 mo	1
Lamo-Espinosa (2016) ⁸⁷ Lamo-Espinosa J.M. Mora G. Blanco J.F. Granero-Molto F. Nunez-Cordoba J.M. Sanchez-Echenique C. et al. Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II). J Transl Med. 2016 Aug 26; 14: 246 Crossref PubMed Scopus (184) Google Scholar	CE BMSC: iliac crest	Hyaluronic acid	Intra-articular injection without radiographic guidance	Low-dose: 10 × 10⁶ High-dose: 100 × 10⁶	3, 6, 12 mo	2
Turajane (2017) ⁹³ Turajane T. Chaveewanakorn U. Fongsarun W. Aojanepong J. Papadopoulos K.I. 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 Cell Int. 2017; 2017: 8925132 PubMed Google Scholar	PBSC	Hyaluronic acid, GFA (PRP, hG-CSF)	Arthroscopic microdrilling (group 1, 2) followed by intra-operative, intra-articular injection of: Group 1: PBSC, GFA, HA Group 2: PBSC, PRP, HA Group 3: HA only	3 ml PBSC Range TNC: 1.095–1.276 × 10⁶	1, 6, 12 mo	3
Vega (2015) ⁹⁴ Vega A. Martin-Ferrero M.A. Del Canto F. Alberca M. Garcia V. Munar A. et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation. 2015 Aug; 99: 1681-1690 Crossref PubMed Scopus (383) Google Scholar	Allogeneic culture-expanded BMSC: iliac crest	n/a	Intra-articular injection without radiographic guidance	40 × 10⁶	8 days, 3, 6, 12 mo	1
Centeno (2014) ⁸⁸ Centeno C.J. Freeman M.D. Percutaneous injection of autologous, culture-expanded mesenchymal stem cells into carpometacarpal hand joints: a case series with an untreated comparison group. Wien Med Wochenschr (1946). 2014 Mar; 164: 83-87 Crossref PubMed Scopus (21) Google Scholar	CE BMSC: iliac crest	Platelet lysate	Intra-articular injection with radiographic and fluoroscopic guidance	5.76 × 10⁶	3, 6, & 12 mo	1
Jo (2014) ¹³ Jo C.H. Lee Y.G. Shin W.H. Kim H. Chai J.W. Jeong E.C. et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem cell (Dayton, Ohio). 2014 May; 32: 1254-1266 Crossref PubMed Scopus (597) Google Scholar	CE ADSC: SQ abdominal fat	n/a	Intra-articular injection with 3 mL saline	Low-dose: 10 × 10⁶ Mid-dose: 50 × 10⁶ High-dose: 100 × 10⁶	6 mo	1
Jo (2017) ⁹⁰ Jo C.H. Chai J.W. Jeong E.C. Oh S. Shin J.S. Shim H. et al. 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 Oct; 45: 2774-2783 Crossref PubMed Scopus (130) Google Scholar	CE ADSC: SQ abdominal fat	n/a	Intra-articular injection with 3 mL saline	Low-dose: 10 × 10⁶ Mid-dose: 50 × 10⁶ High-dose: 100 × 10⁶	12, 24 mo	1
Koh (2014) ⁹¹ Koh Y.G. Kwon O.R. Kim Y.S. Choi Y.J. 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: J Arthroscopic Relat Dis: Off Pub Arthroscopy Assoc North America Int Arthroscopy Assoc. 2014 Nov; 30: 1453-1460 Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar	SVF/ADSC: SQ buttocks	PRP	Intra-articular arthroscopic-guided injection followed by open-wedge HTO	120 ml of SVF Estimated 8.5% of 4.83 × 10⁷ SVF cells (4.11 × 10⁶)	Mean 24.2 ± 4.7 mo	1
Nguyen (2016) ³⁰ Nguyen P.D. Tran T.D. Nguyen H.T. Vu H.T. Le P.T. Phan N.L. et al. Comparative clinical observation of arthroscopic microfracture in the presence and absence of a stromal vascular fraction injection for osteoarthritis. Stem Cells Transl Med. 2017 Jan; 6: 187-195 Crossref PubMed Scopus (62) Google Scholar	SVF/ADSC: SQ abdominal fat	PRP	Intra-articular injection with 5 ml SVF + PRP	10⁷ SVF cells/ml	1, 6, 12, 18 mo	1
Pers (2016) ⁹⁷ Pers Y.M. Rackwitz L. Ferreira R. Pullig O. Delfour C. Barry F. et al. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial. Stem Cells Transl Med. 2016 Jul; 5: 847-856 Crossref PubMed Scopus (317) Google Scholar	CE ADSC: SQ abdominal fat	n/a	Intra-articular injection with ultrasound guidance	Low-dose: 2 × 10⁶ Mid-dose: 10 × 10⁶ High-dose: 50 × 10⁶	6 mo	1
Shapiro (2017) ⁹² Shapiro S.A. Kazmerchak S.E. Heckman M.G. Zubair A.C. O'Connor M.I. A prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis. Am J Sports Med. 2017 Jan; 45: 82-90 Crossref PubMed Scopus (168) Google Scholar	BMAC/BMSC: iliac crest	Platelet-poor bone marrow plasma	Ultrasound guided intra-articular injection of 5 ml BMAC with 10 ml platelet-poor bone marrow plasma	Median of 3.4 × 10⁴ MSCs and 4.62 × 10⁶ hematopoietic stem cells	1 wk, 3 mo, 6 mo	1
Wakitani (2002) ⁹⁵ Wakitani S. Imoto K. Yamamoto T. Saito M. Murata N. Yoneda M. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthritis Cartilage/OARS, Osteoarthritis Res Soc. 2002 Mar; 10: 199-206 Abstract Full Text PDF PubMed Scopus (795) Google Scholar	CE BMSC: iliac crest	Collagen gel sheet	HTO followed by collagen cell sheet with cells implanted	1.3 × 10⁷	Mean: 16 months	1
Wong (2013) ⁹⁶ Wong K.L. Lee K.B. Tai B.C. Law P. Lee E.H. Hui J.H. 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: J Arthroscopic Relat Sur: Off Pub Arthroscopy Assoc North America Int Arthroscopy Assoc. 2013 Dec; 29: 2020-2028 Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar	CE BMSC: iliac crest	Hyaluronic acid	HTO and microfracture followed 3 weeks later with intra-articular injection with 2 ml HA	1.46 ± 0.29 × 10⁶	every 6 weeks for 6 mo, 1, 2 yrs	1 MSC 3 HA

ADSC = adipose-derived stem cell; BMSC = bone-marrow stem cell; MSC = mesenchymal stem cell; PBSC = peripheral blood stem cell; SQ = subcutaneous; HA = hyaluronic acid; CE = culture-expanded; TNC = total nucleated cells; HTO = high tibial osteotomy.

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Outcome assessments

All 61 clinical studies reported some level of improvement of OA symptoms from baseline in the MSC therapy group. Main findings of outcome assessments in level I and II studies can be found in Table V

¹³

Jo C.H.
Lee Y.G.
Shin W.H.
Kim H.
Chai J.W.
Jeong E.C.
et al.

Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial.

^,

²⁹

Garay-Mendoza D.
Villarreal-Martinez L.
Garza-Bedolla A.
Perez-Garza D.M.
Acosta-Olivo C.
Vilchez-Cavazos F.
et al.

The effect of intra-articular injection of autologous bone marrow stem cells on pain and knee function in patients with osteoarthritis.

^,

³⁰

Nguyen P.D.
Tran T.D.
Nguyen H.T.
Vu H.T.
Le P.T.
Phan N.L.
et al.

Comparative clinical observation of arthroscopic microfracture in the presence and absence of a stromal vascular fraction injection for osteoarthritis.

^,

⁸⁷

Lamo-Espinosa J.M.
Mora G.
Blanco J.F.
Granero-Molto F.
Nunez-Cordoba J.M.
Sanchez-Echenique C.
et al.

Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II).

. Although there was overlap between outcome measures between included Level I and II articles, no meta-analysis was performed due to the diversity of metrics and outcomes. The most common measures were VAS (n = 10), WOMAC (n = 9), safety (n = 6) and radiologic evidence (n = 5).

Table VOutcome assessments of the included level I and II evidence studies

First Author (Date of publication)	Comparison groups	Outcomes measures	MSC group scores: Baseline vs Final F/U (x ± SD)	MSC-groups significant improvement from baseline	Comparison group scores: Baseline vs Final F/U	Significant improvement with comparison
Garay-Mendoza (2017) ⁴⁵ Buda R. Castagnini F. Cavallo M. Ramponi L. Vannini F. Giannini S. One-step" bone marrow-derived cells transplantation and joint debridement for osteochondral lesions of the talus in ankle osteoarthritis: clinical and radiological outcomes at 36 months. Arch Orthop Trauma Surg. 2016; 136: 107-116 Crossref PubMed Scopus (24) Google Scholar	Acetaminophen 500 mg every 8 h for 6 months	VAS	5.27 ± 2.196 vs 0.92 ± 1.29		4.32 ± 2.35 vs 4.64 ± 2.43	Yes, P < 0.0001
		WOMAC ∗ This study considered at WOMAC scale of 0–100, with a score of 100 indicating the best outcomes.	62.61 ± 18.55 vs 91.73 ± 9.45		6.93 ± 17.89 vs 72.96 ± 15.04	Yes, P < 0.0001
		Safety	Swelling, pain, stiffness		Swelling, pain, stiffness
Gupta (2016) ⁸⁹ Gupta P.K. Chullikana A. Rengasamy M. Shetty N. Pandey V. Agarwal V. et al. Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel(R)): preclinical and clinical trial in osteoarthritis of the knee joint. Arthritis Res Ther. 2016 Dec 20; 18: 301 Crossref PubMed Scopus (181) Google Scholar	Dose-escalation cohorts Placebo: injection of PLASMA-LYTE A	VAS	Low dose: 60.9 ± 19.7 vs 20.6 ± 17.3 Low dose: 73.7 ± 15.2 vs 45.3 ± 31.0 High dose: 57.4 ± 29.0 vs 37.1 ± N/A High dose: 46.6 ± 23.6 vs 43.6 ± N/A	No, P > 0.05 due to small sample size	Placebo cohort 1: 61.0 ± 23.8 vs 39.7 ± 28.3 Placebo cohort 2: 65.3 ± 12.2 vs 43.4 ± N/A	No, P = 0.24 No, P = 0.11
		ICOAP	Low dose: 45.7 ± 19.2 vs 21.4 ± 21.2 Low dose: 59.3 ± 21.7 vs 12.3 ± 27.4 High dose: 58.4 ± 20.7 vs N/A High dose: 46.4 ± 22.0 vs N/A	No, P > 0.05 due to small sample size	Placebo cohort 1: 49.3 ± 18.7 vs 7.5 ± 27.1 Placebo cohort 2: 54.8 ± 17.8 vs N/A	No, P = 0.38 No, P = 0.54
		WOMAC	Low dose: 1315.8 ± 444.8 vs 717.8 ± 503.8 Low dose: 1498.4 ± 407.4 vs 359.9 ± 786.4 High dose: 1470.6 ± 471.0 vs N/A High dose: 1388.1 ± 508.8 vs N/A	No, P > 0.05 due to small sample size	Placebo cohort 1: 1239.6 ± 472.2 vs 233.8 ± 641.9 Placebo cohort 2: 1392.0 ± 324.7 vs N/A	No, P = 0.28 No, P = 0.9
		Radiographic (WORMS)	Low dose: 67.0 ± 19.2 vs 66.1 ± 19.2 Low dose: 78.8 ± 40.9 vs 78.0 ± 41.1 High dose: 71.3 ± 21.4 vs 67.0 ± 15.7 High dose: 70.8 ± 14.7 vs 72.3 ± 15.2	N/A	Placebo cohort 1: 76.5 ± 23.5 vs 74.9 ± 22.5 Placebo cohort 2: 70.8 ± 14.7 vs 72.3 ± 15.3	No, P = 0.5310 No, P = 0.0609
		Safety	Pain and swelling One serious event: synovial effusion	N/A	Pain and swelling	N/A
Lamo-Espinosa (2016) ⁸⁷ Lamo-Espinosa J.M. Mora G. Blanco J.F. Granero-Molto F. Nunez-Cordoba J.M. Sanchez-Echenique C. et al. Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II). J Transl Med. 2016 Aug 26; 14: 246 Crossref PubMed Scopus (184) Google Scholar	Dose escalation cohorts Placebo: HA alone	VAS (IQR)	Low dose: 7 (5,8) vs 2 (1,3) High dose: 6(4,8) vs 2 (0,4)	N/A	5 (3,7) vs 4 (3,5)	With low dose cohort: Yes, P = 0.005 With high dose cohort: Yes, P < 0.009
		WOMAC	Low dose: 37 (11,37) vs 21.5 (15,26) High dose: 28 (16,34) vs 16.5 (12,19)	No, P > 0.05 Yes, P < 0.01	29 (19,38) vs 13.5 (8,33)	N/A
		Radiographic (WORMS, X-Ray)	MRI (WORMS): decreased joint damage X-Ray: no change in joint space width	N/A	MRI (WORMS): no change in joint damage X-Ray: reduction in joint space width	N/A
		Knee Flexion and Extension Measurements	Flexion measurement: Low dose: 116 (110,116) vs 119 (116,122) High dose: 110 (110,117) vs 118(116, 122) Extension measurement: Low dose: 176 (173,180) vs 180 (176, 180) High dose: 177 (174,180) vs 180 (180,180)	Yes, P < 0.05 Yes, P < 0.05 Yes, P < 0.05 Yes, P < 0.05	Flexion: 118 (114,120) vs 118 (115,118) Extension: 180 (176, 180) vs 179 (175, 180)	N/A
		Safety	No adverse events besides mild pain	N/A	No adverse events besides mild pain	N/A
Turajane (2017) ⁹³ Turajane T. Chaveewanakorn U. Fongsarun W. Aojanepong J. Papadopoulos K.I. 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 Cell Int. 2017; 2017: 8925132 PubMed Google Scholar	Cohort 1: PBSCs, HA, PRP, hG-CSF, and microdrilling treatment Cohort 2: like cohort 1 but without hG-CSF Placebo: HA alone	Need for surgical intervention at 12 months	Cohort 1:0 patients need joint replacement Cohort 2:0 patients need joint replacement	N/A	3 need joint replacement	Yes, P < 0.033
		WOMAC	Cohort 1: 218.5 vs 52 Cohort 2: 212.2 vs 75	Yes, P < 0.0001 Yes, P < 0.0001	215.3 vs 126.8	With cohort 1: Yes, P < 0.001 With cohort 2: Yes, P < 0.001
Vega (2015) ⁹⁴ Vega A. Martin-Ferrero M.A. Del Canto F. Alberca M. Garcia V. Munar A. et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation. 2015 Aug; 99: 1681-1690 Crossref PubMed Scopus (383) Google Scholar	Placebo: HA alone	VAS^SE	54 ± 7 vs 33 ± 6	N/A	64 ± 7 vs 51 ± 8	Yes, P < 0.005
		WOMAC^SE	41 ± 3 vs 28 ± 5	N/A	45 ± 3 vs 41 ± 6	Yes, P < 0.005
		Lequesne score^SE	39 ± 4 vs 30 ± 3	N/A	45 ± 4 vs 42 ± 5	Yes, P < 0.005
		SF-12 PCS	40 ± 9 vs 45 ± 11	No, P > 0.05	35 ± 8 vs 40 ± 8	No, P > 0.05
		SF-12 MCS	54 ± 10 vs 51 ± 12	No, P > 0.05	49 ± 9 vs 47 ± 11	No, P > 0.05
		MRI (PCI)	Decreased significantly by 1 year	Yes, P < 0.05	Does not drop significantly by 1 year	No, P > 0.05
		Safety	Inflammation during first 7 days	N/A	Inflammation during first 7 days	N/A
Centeno (2014) ⁸⁸ Centeno C.J. Freeman M.D. Percutaneous injection of autologous, culture-expanded mesenchymal stem cells into carpometacarpal hand joints: a case series with an untreated comparison group. Wien Med Wochenschr (1946). 2014 Mar; 164: 83-87 Crossref PubMed Scopus (21) Google Scholar	Untreated procedure candidates (No placebo)	−100% to +100% pain relief scale	60% improvement		19 % improvement	Yes, P = 0.03
	Untreated procedure candidates (No placebo)	VAS	63% improvement (5.2 vs 2.0)
Jo (2014) ¹³ Jo C.H. Lee Y.G. Shin W.H. Kim H. Chai J.W. Jeong E.C. et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem cell (Dayton, Ohio). 2014 May; 32: 1254-1266 Crossref PubMed Scopus (597) Google Scholar	Dose-escalation cohorts (No placebo)	WOMAC^SE	Low dose: 43.4 ± 12.7 vs 25.3 ± 19.5 Mid-dose: 69.0 ± 5.9 vs 48.5 ± 11.0 High dose: 54.2 ± 5.2 vs 32.8 ± 6.3	No, P = 0.339 No, P = 0.391 Yes, P = 0.003	N/A	N/A
		Safety	No treatment-related adverse events	N/A	N/A	N/A
		VAS	Low dose: 70.0 ± 10.0 vs 48.3 ± 14.8 Mid-dose: 78.3 ± 1.7 vs 67.5 ± 11.5 High dose: 79.6 ± 2.2 vs 44.2 ± 6.3	No, P = 0.069 No, P = 0.486 Yes, P = 0.000	N/A	N/A
		KSS Knee score KSS Function score	Low dose: 41.3 ± 6.8 vs 79.0 ± 12.5 Mid-dose: 35.3 ± 9.8 vs 47.3 ± 6.8 High dose: 47.2 ± 2.6 vs 71.0 ± 4.4 Low dose: 60.0 ± 5.8 vs 83.3 ± 8.8 Mid-dose: 56.7 ± 6.7 vs 70.0 ± 7.6 High dose: 70.8 ± 2.6 vs 77.5 ± 2.5	Yes, P = 0.025 No, P = 0.324 Yes, P = 0.000 Yes, P = 0.020 No, P = 0.333 No, P = 0.120	N/A N/A	N/A N/A
		Radiographic: depth of cartilage defect, Radiographic: articular cartilage volume)	High dose cohort, (at medial femoral and tibial condyles): 497.9 ± 29.7 vs 297.9 ± 51.2 333.2 ± 51.2 vs 170.6 ± 48.2 High dose cohort, (at medial femoral and tibial condyles): 3313.7 ± 304.1 vs 3780.6 ± 284.4 1157.5 ± 145.8 vs 1407.7 ± 150.5	Yes, P < .05 Yes, P < 0.05	N/A	N/A
				Yes, P < .05 Yes, P < 0.05	N/A	N/A
Jo (2017)⁹³	Dose-escalation cohorts (No placebo)	WOMAC	Low dose: 43.3 ± 12.7 vs 17.0 ± 9.8 Mid-dose: 69.0 ± 5.9 vs 25.1 ± 11.0 High dose: 54.2 ± 5.2 vs 19.0 ± 5.5	No, P = 0.083 No, P = 0.210 Yes, P < 0.001	N/A	N/A
		VAS	Low dose: 70.0 ± 10.0 vs 40.0 ± 15.3 Mid-dose: 78.3 ± 1.7 vs 66.0 ± 14.7 Low dose: 79.6 ± 2.2 vs 45.8 ± 8.1	Yes, P = 0.035 No, P = 0.601 Yes, P = 0.002	N/A	N/A
		KSS Knee score KSS Function score	Low dose: 41.3 ± 6.8 vs 71.0 ± 12.1 Mid-dose 35.3 ± 9.8 vs 70.8 ± 12.8 High dose: 47.2 ± 2.6 vs 79.3 ± 4.7 Low dose: 60.0 ± 5.8 vs 86.7 ± 3.3 Mid-dose: 56.7 ± 6.7 vs 73.3 ± 11. High dose: 70.8 ± 2.6 vs 83.3 ± 3.8	Yes, P = 0.031 No, P = 0.241 Yes, P =< 0.001 Yes. P = 0.015 No, P = 0.439 Yes, P = 0.026 But, plateaus at 1 year F/U	N/A N/A	N/A N/A
		KOOS pain score KOOS symptom score KOOS activities of daily living score	Low dose: 49.1 ± 4.0 vs 69.4 ± 12.7 Mid-dose: 30.6 ± 12.1 vs 61.0 ± 9.9 High dose: 32.6 ± 4.1 vs 76.4 ± 5.4 Low dose: 61.9 ± 7.2 vs 72.6 ± 5.2 Mid-dose: 39.3 ± 16.4 vs 76.9 ± 10.5 High dose: 48.5 ± 5.3 vs 72.9 ± 5.2 Low dose: 58.8 ± 10.0 vs 81.9 ± 9.7 Mid-dose: 22.5 ± 6.0 vs 73.1 ± 12.7 High dose: 28.6 ± 3.6 vs 33.9 ± 3.0	No, P = 0.148 No, P = 0.220 Yes, P < 0.001 Yes, P = 0.035 No, P = 0.214 Yes, P = 0.003 Yes, P = 0.001 No, P = 0.237 Yes, P < 0.001	N/A N/A N/A	N/A N/A N/A
		Radiographic (MRI)	No significant change in joint space width, mechanical or anatomic axis. Low dose: no significant change in cartilage defect High dose: regenerated cartilage 6 months. not 2 years	Yes, P < 0.05 † At medial and lateral femoral and tibial condyles and at 6 months, at medial femoral and lateral tibial condyle at 2 years.	N/A	N/A
Koh (2014) ⁹¹ Koh Y.G. Kwon O.R. Kim Y.S. Choi Y.J. 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: J Arthroscopic Relat Dis: Off Pub Arthroscopy Assoc North America Int Arthroscopy Assoc. 2014 Nov; 30: 1453-1460 Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar	PRP alone	VAS	44.3 ± 5.7 vs 10.2 ± 5.7	N/A	45.4 ± 7.1 vs 16.2 ± 4.6	Yes, P < 0.001
		KOOS pain scale KOOS symptom scale	81.2 ± 6.9 vs N/A 82.8 7.2 vs N/A	N/A	74.0 ± 5.7 75.4 ± 8.5	Yes, P < 0.001 Yes, P = 0.006
		Lysholm score	55.7 ± 11.5 vs 84.7 ± 16.2	N/A	56.7 ± 12.2 vs 80.6 ± 13.5	No, P = 0.357
		Radiographic (FTA and WBL)	Varus 3.4 ± 3.0 vs Valgus 8.7 ± 2.3 17.7 ± 7.3 vs 61.1 ± 3.4	N/A	Varus 2.8 ± 1.7 vs Valgus 9.8 ± 2.4 16.1 ± 5.7 vs 60.3 ± 3.0	No, P > 0.05 No, P > 0.05
Nguyen (2016) ³⁰ Nguyen P.D. Tran T.D. Nguyen H.T. Vu H.T. Le P.T. Phan N.L. et al. Comparative clinical observation of arthroscopic microfracture in the presence and absence of a stromal vascular fraction injection for osteoarthritis. Stem Cells Transl Med. 2017 Jan; 6: 187-195 Crossref PubMed Scopus (62) Google Scholar	Arthroscopic microfracture alone	WOMAC	42.87 ± 16.29 vs 17.33 ± 14.91	N/A	47.37 ± 17.13 vs 37.08 ± 21.45	Yes, P < 0.05
		Lysolm score	53.47 ± 14.56 vs 84.73 ± 19.54	N/A	64.13 ± 10.19 vs 65.17 ± 14.74	Yes, P < 0.05
		VAS for pain	1.60 ± 0.83 vs 3.47 ± 0.74	Yes, P < 0.05	2.67 6 0.62 vs 1.40 6 0.51	Yes, P < 0.05
		Modified Outerbridge classification	3.33 ± 0.97 vs 2.93 ± 0.88	N/A	2.67 ± 1.35 vs 4.02 ± 1.08	No, P > 0.05 Note: scores increase in placebo, decrease if treated
Pers (2016) ⁹⁷ Pers Y.M. Rackwitz L. Ferreira R. Pullig O. Delfour C. Barry F. et al. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial. Stem Cells Transl Med. 2016 Jul; 5: 847-856 Crossref PubMed Scopus (317) Google Scholar	Dose-escalation cohorts (No placebo)	Safety	Only one severe adverse event (UA in a patient with multiple risk factors)	N/A	N/A	N/A
		VAS	Low dose: 77 ± 15.7 vs ± 35.8 ± 13.3 Mid-dose: 63.7 ± 20.5 vs 36.7 ± 11.9 High dose: 43.7 ± 25.4 vs 24 ± 17.1	Yes, P < 0.05 No, P = 0.09 No, P = 0.54	N/A	N/A
		WOMAC	Low dose: 60.7 ± 18.6 vs 27.6 ± 8.9 Mid-dose: 47.2 ± 14.7 vs 24.3 ± 9.1 High dose: 38.8 ± 27.3 vs 6.2 ± 16.0	Yes, P < 0.001 No, P = 0.054 No, P = 0.38	N/A	N/A
		KOOS	Low dose: 34 ± 15 vs 65.8 ± 9.1 Mid-dose: 42 ± 9 vs 59.2 ± 6.5 High dose: 45.2 ± 13.6 vs 65.2 ± 13.1	Yes, P < 0.01 Yes, P < 0.05 No, P = 0.32	N/A	N/A
		SF-36 PCS SF-36 MCS	Low dose: 30.9 ± 8.2 vs 39.1 ± 4.6 Mid-dose: 29.9 ± 6.2 vs 35.3 ± 4.0 High dose: 35.7 ± 10.6 vs 37.6 ± 6.8 Low dose: 55.9 ± 8.3 vs 51.9 ± 3.8 Mid-dose: 51.9 ± 10.2 vs 55.1 ± 5.8 High dose: 53.6 ± 7.8 vs 54.1 ± 6.6	No, P = 0.33 No, P = 0.42 No, P = 0.98 No, P = 0.60 No, P = 0.91 No, P = 0.99	N/A N/A	N/A N/A
Shapiro (2017) ⁹² Shapiro S.A. Kazmerchak S.E. Heckman M.G. Zubair A.C. O'Connor M.I. A prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis. Am J Sports Med. 2017 Jan; 45: 82-90 Crossref PubMed Scopus (168) Google Scholar	Saline into each patient's contralateral knee. Patient blinded to knee with treatment vs placebo.	VAS for pain	3.1 vs 1.5	Yes, P = 0.001	2.9 vs 0.8	No, P = 0.44
		ICOAP	32 vs 16	Yes, P = 0.0005	32 vs 9	No, P = 0.54
		Activity level	No/mild limits: 6 vs 15 Moderate limits: 13 vs 9 Severe/extreme limits: 6 vs 1	Yes, P = 0.0003	No/mild limits: 8 vs 17 Moderate limits: 11 vs 5 Severe/extreme limits: 6 vs 3	No, P = 0.51
Wakitani (2002) ⁹⁵ Wakitani S. Imoto K. Yamamoto T. Saito M. Murata N. Yoneda M. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthritis Cartilage/OARS, Osteoarthritis Res Soc. 2002 Mar; 10: 199-206 Abstract Full Text PDF PubMed Scopus (795) Google Scholar	Cell-free collagen gel-sheet implantation	HSS Knee Rating Scale	65.0 ± 6.7 vs 81.3 ± 8.6	Yes, P = 0.0029	66.3 ± 10.5 vs 79.2 ± 8.7	No, P > 0.05
	Cell-free collagen gel-sheet implantation	Arthroscopic/histologic cartilage evaluation	9.8 ± 2.0 vs 15.4 ± 1.4		7.5 ± 2.2 vs 10.0 ± 6.1 8.0 ± 0.9 vs 11.3 ± 2.3	Yes, P < 0.05
Wong (2013) ⁹⁶ Wong K.L. Lee K.B. Tai B.C. Law P. Lee E.H. Hui J.H. 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: J Arthroscopic Relat Sur: Off Pub Arthroscopy Assoc North America Int Arthroscopy Assoc. 2013 Dec; 29: 2020-2028 Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar	HTO + HA alone	Lysholm scoreⁱ	41.9 ± 19.2 vs N/A Improvement of 7.61	Yes, P = 0.016	50.4 ± 23.0 vs N/A	Yes, P = 0.016
		IKDCⁱ	33.9 ± 11.4 vs N/A Improvement of 7.65	Yes, P = 0.001	36.0 ± 13.7 vs N/A	Yes, P = 0.001
		Radiographic (MOCART)	62.32 ± 17.56		43.21 ± 13.55	Yes, P < 0.001

F/U = follow-up; VAS = visual analog scale; ICOAP = intermittent and constant osteoarthritis pain; WOMAC = Western Ontario and McMaster Universities Osteoarthritis index; WORMS = whole organ magnetic resonance imaging score; MSC = mesenchymal stem cells; SD/SE = standard deviation/standard error; HA = hyaluronic acid; PBSC = peripheral blood stem cell; PRP = platelet-rich plasm; hG-CSF = granulocyte colony stimulating factor; SF-12/36 PCS = standard form 12/36 physical component score; SF-12/36 MCS = standard form 12/36 mental component score; PCI = poor cartilage index; KSS = Knee Society clinical rating system score; KOOS = Knee injury and osteoarthritis outcome score; MRI = magnetic resonance imaging; FTA = femotibial angle; WBL = weight-bearing line; HSS = Hospital for Special Surgery; IKDC = international knee documentation committee score; MOCART = magnetic resonance observation of cartilage repair tissue score; UA = unstable angina; HTO = high tibial osteotomy; N/A = not available; IQR = interquartile range.

^SE study reported standard error instead of standard deviation for this outcome measure.

∗ This study considered at WOMAC scale of 0–100, with a score of 100 indicating the best outcomes.

† At medial and lateral femoral and tibial condyles and at 6 months, at medial femoral and lateral tibial condyle at 2 years.

Open table in a new tab

Of the ten level I and II evidence studies that measured VAS for pain, patients in all of the studies exhibited VAS score improvements

²⁹

Garay-Mendoza D.
Villarreal-Martinez L.
Garza-Bedolla A.
Perez-Garza D.M.
Acosta-Olivo C.
Vilchez-Cavazos F.
et al.

The effect of intra-articular injection of autologous bone marrow stem cells on pain and knee function in patients with osteoarthritis.

^,

³⁰

Nguyen P.D.
Tran T.D.
Nguyen H.T.
Vu H.T.
Le P.T.
Phan N.L.
et al.

Comparative clinical observation of arthroscopic microfracture in the presence and absence of a stromal vascular fraction injection for osteoarthritis.

^,

⁸⁷

Lamo-Espinosa J.M.
Mora G.
Blanco J.F.
Granero-Molto F.
Nunez-Cordoba J.M.
Sanchez-Echenique C.
et al.

Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II).

^,

⁸⁸

Centeno C.J.
Freeman M.D.

Percutaneous injection of autologous, culture-expanded mesenchymal stem cells into carpometacarpal hand joints: a case series with an untreated comparison group.

^,

⁸⁹

Gupta P.K.
Chullikana A.
Rengasamy M.
Shetty N.
Pandey V.
Agarwal V.
et al.

Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel(R)): preclinical and clinical trial in osteoarthritis of the knee joint.

^,

⁹⁰

Jo C.H.
Chai J.W.
Jeong E.C.
Oh S.
Shin J.S.
Shim H.
et al.

Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a 2-year follow-up study.

^,

⁹¹

Koh Y.G.
Kwon O.R.
Kim Y.S.
Choi Y.J.

Comparative outcomes of open-wedge high tibial osteotomy with platelet-rich plasma alone or in combination with mesenchymal stem cell treatment: a prospective study.

^,

⁹²

Shapiro S.A.
Kazmerchak S.E.
Heckman M.G.
Zubair A.C.
O'Connor M.I.

A prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis.

^,

⁹⁴

Vega A.
Martin-Ferrero M.A.
Del Canto F.
Alberca M.
Garcia V.
Munar A.
et al.

Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial.

^,

⁹⁷

Pers Y.M.
Rackwitz L.
Ferreira R.
Pullig O.
Delfour C.
Barry F.
et al.

Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial.

. In four of these studies, VAS improved compared to placebo

²⁹

Garay-Mendoza D.
Villarreal-Martinez L.
Garza-Bedolla A.
Perez-Garza D.M.
Acosta-Olivo C.
Vilchez-Cavazos F.
et al.

The effect of intra-articular injection of autologous bone marrow stem cells on pain and knee function in patients with osteoarthritis.

^,

³⁰

Nguyen P.D.
Tran T.D.
Nguyen H.T.
Vu H.T.
Le P.T.
Phan N.L.
et al.

Comparative clinical observation of arthroscopic microfracture in the presence and absence of a stromal vascular fraction injection for osteoarthritis.

^,

⁸⁷

Lamo-Espinosa J.M.
Mora G.
Blanco J.F.
Granero-Molto F.
Nunez-Cordoba J.M.
Sanchez-Echenique C.
et al.

Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II).

^,

⁹¹

Koh Y.G.
Kwon O.R.
Kim Y.S.
Choi Y.J.

Comparative outcomes of open-wedge high tibial osteotomy with platelet-rich plasma alone or in combination with mesenchymal stem cell treatment: a prospective study.

^,

⁹⁴

Vega A.
Martin-Ferrero M.A.
Del Canto F.
Alberca M.
Garcia V.
Munar A.
et al.

Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial.

. Lamo-Espinosa et al.

⁸⁷

Lamo-Espinosa J.M.
Mora G.
Blanco J.F.
Granero-Molto F.
Nunez-Cordoba J.M.
Sanchez-Echenique C.
et al.

Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II).

found the high-dose BMSC-treated patients’ VAS improved significantly (P < 0.01) compared to placebo of HA alone. Garay-Mendoza et al.

²⁹

Garay-Mendoza D.
Villarreal-Martinez L.
Garza-Bedolla A.
Perez-Garza D.M.
Acosta-Olivo C.
Vilchez-Cavazos F.
et al.

The effect of intra-articular injection of autologous bone marrow stem cells on pain and knee function in patients with osteoarthritis.

found VAS improvements at 1 week (P = 0.0003), 1 month (P < 0.0001), and 6 months (P < 0.0001). Notably, the BMSC-treated group VAS pain score (0.92 ± 1.29) was lower compared to the daily acetaminophen placebo group (4.64 ± 2.43). Vega et al.

⁹⁴

Vega A.
Martin-Ferrero M.A.
Del Canto F.
Alberca M.
Garcia V.
Munar A.
et al.

Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial.

found BMSC-treated patients demonstrated significant VAS improvement at 6 months, whereas placebo HA-treated patients did not significantly improve until 12 months. Similarly, Koh et al.

⁹¹

Koh Y.G.
Kwon O.R.
Kim Y.S.
Choi Y.J.

Comparative outcomes of open-wedge high tibial osteotomy with platelet-rich plasma alone or in combination with mesenchymal stem cell treatment: a prospective study.

found that both ADSC-treated patients and PRP-placebo patients improved their VAS scores at 6 and 12 months, but the ADSC-treated group demonstrated a greater VAS improvement (10.2 ± 5.7) than the placebo group (16.2 ± 4.6). Additionally, Nguyen et al.

³⁰

Nguyen P.D.
Tran T.D.
Nguyen H.T.
Vu H.T.
Le P.T.
Phan N.L.
et al.

Comparative clinical observation of arthroscopic microfracture in the presence and absence of a stromal vascular fraction injection for osteoarthritis.

found the ADSC-treated group (3.47 ± 0.74) improved significantly compared to the microfracture placebo group (2.08 ± 1.08). The remaining studies measuring VAS exhibited improvement upon follow-up but the improvement was either not statistically significant

⁸⁹

Gupta P.K.
Chullikana A.
Rengasamy M.
Shetty N.
Pandey V.
Agarwal V.
et al.

Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel(R)): preclinical and clinical trial in osteoarthritis of the knee joint.

, not compared to the placebo

⁸⁸

Centeno C.J.
Freeman M.D.

Percutaneous injection of autologous, culture-expanded mesenchymal stem cells into carpometacarpal hand joints: a case series with an untreated comparison group.

, or there was no placebo to compare to

⁹⁰

Jo C.H.
Chai J.W.
Jeong E.C.
Oh S.
Shin J.S.
Shim H.
et al.

Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a 2-year follow-up study.

^,

⁹⁷

Pers Y.M.
Rackwitz L.
Ferreira R.
Pullig O.
Delfour C.
Barry F.
et al.

Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial.

. One study showed VAS improvement with MSC treatment but no significance when compared to saline injection placebo (P > 0.09)

⁹²

Shapiro S.A.
Kazmerchak S.E.
Heckman M.G.
Zubair A.C.
O'Connor M.I.

A prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis.

.

All level I and II studies that measured WOMAC also saw improvements upon follow-up

¹³

Jo C.H.
Lee Y.G.
Shin W.H.
Kim H.
Chai J.W.
Jeong E.C.
et al.

Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial.

^,

²⁹

Garay-Mendoza D.
Villarreal-Martinez L.
Garza-Bedolla A.
Perez-Garza D.M.
Acosta-Olivo C.
Vilchez-Cavazos F.
et al.

The effect of intra-articular injection of autologous bone marrow stem cells on pain and knee function in patients with osteoarthritis.

^,

³⁰

Nguyen P.D.
Tran T.D.
Nguyen H.T.
Vu H.T.
Le P.T.
Phan N.L.
et al.

Comparative clinical observation of arthroscopic microfracture in the presence and absence of a stromal vascular fraction injection for osteoarthritis.

^,

⁸⁷

Lamo-Espinosa J.M.
Mora G.
Blanco J.F.
Granero-Molto F.
Nunez-Cordoba J.M.
Sanchez-Echenique C.
et al.

Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II).

^,

⁸⁹

Gupta P.K.
Chullikana A.
Rengasamy M.
Shetty N.
Pandey V.
Agarwal V.
et al.

Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel(R)): preclinical and clinical trial in osteoarthritis of the knee joint.

^,

⁹⁰

Jo C.H.
Chai J.W.
Jeong E.C.
Oh S.
Shin J.S.
Shim H.
et al.

Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a 2-year follow-up study.

^,

⁹³

Turajane T.
Chaveewanakorn U.
Fongsarun W.
Aojanepong J.
Papadopoulos K.I.

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.

^,

⁹⁴

Vega A.
Martin-Ferrero M.A.
Del Canto F.
Alberca M.
Garcia V.
Munar A.
et al.

Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial.

. Lamo-Espinosa et al.

⁸⁷

Lamo-Espinosa J.M.
Mora G.
Blanco J.F.
Granero-Molto F.
Nunez-Cordoba J.M.
Sanchez-Echenique C.
et al.

Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II).

showed improved WOMAC scores in high-dose BMSC-treated patients than in the HA placebo group (P < 0.01). Garay-Mendoza et al.

²⁹

Garay-Mendoza D.
Villarreal-Martinez L.
Garza-Bedolla A.
Perez-Garza D.M.
Acosta-Olivo C.
Vilchez-Cavazos F.
et al.

The effect of intra-articular injection of autologous bone marrow stem cells on pain and knee function in patients with osteoarthritis.

reported similar improvement compared to acetaminophen placebo. Turajane et al.

⁹³

Turajane T.
Chaveewanakorn U.
Fongsarun W.
Aojanepong J.
Papadopoulos K.I.

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.

also found significantly better WOMAC scores in PBSC-treated groups (WOMAC = 52 or 75) compared to the HA-placebo group (WOMAC = 126.8) at 12 months (P < 0.001). Two studies recorded improved WOMAC scores, but not when compared to placebo groups

⁸⁹

Gupta P.K.
Chullikana A.
Rengasamy M.
Shetty N.
Pandey V.
Agarwal V.
et al.

Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel(R)): preclinical and clinical trial in osteoarthritis of the knee joint.

^,

⁹⁴

Vega A.
Martin-Ferrero M.A.
Del Canto F.
Alberca M.
Garcia V.
Munar A.
et al.

Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial.

, and three studies exhibited improved WOMAC but lacked a placebo to compare to

¹³

Jo C.H.
Lee Y.G.
Shin W.H.
Kim H.
Chai J.W.
Jeong E.C.
et al.

Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial.

^,

³⁰

Nguyen P.D.
Tran T.D.
Nguyen H.T.
Vu H.T.
Le P.T.
Phan N.L.
et al.

Comparative clinical observation of arthroscopic microfracture in the presence and absence of a stromal vascular fraction injection for osteoarthritis.

^,

⁹⁰

Jo C.H.
Chai J.W.
Jeong E.C.
Oh S.
Shin J.S.
Shim H.
et al.

Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a 2-year follow-up study.

. In one study, Garay-Mendoza et al.

²⁹

Garay-Mendoza D.
Villarreal-Martinez L.
Garza-Bedolla A.
Perez-Garza D.M.
Acosta-Olivo C.
Vilchez-Cavazos F.
et al.

The effect of intra-articular injection of autologous bone marrow stem cells on pain and knee function in patients with osteoarthritis.

demonstrated that BMSC treatment may lead to higher WOMAC scores (91.27 ± 9.45) compared to acetaminophen placebo (72.35 ± 17.37).

Few serious adverse events were found in level I and II evidence studies that measured safety

¹³

Jo C.H.
Lee Y.G.
Shin W.H.
Kim H.
Chai J.W.
Jeong E.C.
et al.

Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial.

^,

²⁹

Garay-Mendoza D.
Villarreal-Martinez L.
Garza-Bedolla A.
Perez-Garza D.M.
Acosta-Olivo C.
Vilchez-Cavazos F.
et al.

The effect of intra-articular injection of autologous bone marrow stem cells on pain and knee function in patients with osteoarthritis.

^,

⁸⁷

Lamo-Espinosa J.M.
Mora G.
Blanco J.F.
Granero-Molto F.
Nunez-Cordoba J.M.
Sanchez-Echenique C.
et al.

Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II).

^,

⁸⁹

Gupta P.K.
Chullikana A.
Rengasamy M.
Shetty N.
Pandey V.
Agarwal V.
et al.

Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel(R)): preclinical and clinical trial in osteoarthritis of the knee joint.

^,

⁹⁴

Vega A.
Martin-Ferrero M.A.
Del Canto F.
Alberca M.
Garcia V.
Munar A.
et al.

Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial.

^,

⁹⁷

Pers Y.M.
Rackwitz L.
Ferreira R.
Pullig O.
Delfour C.
Barry F.
et al.

Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial.

. Four studies found no serious events as a consequence to MSC-treatment, but patients noted mild pain and swelling post-treatment that was treated with ibuprofen

¹³

Jo C.H.
Lee Y.G.
Shin W.H.
Kim H.
Chai J.W.
Jeong E.C.
et al.

Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial.

^,

²⁹

Garay-Mendoza D.
Villarreal-Martinez L.
Garza-Bedolla A.
Perez-Garza D.M.
Acosta-Olivo C.
Vilchez-Cavazos F.
et al.

The effect of intra-articular injection of autologous bone marrow stem cells on pain and knee function in patients with osteoarthritis.

^,

⁸⁷

Lamo-Espinosa J.M.
Mora G.
Blanco J.F.
Granero-Molto F.
Nunez-Cordoba J.M.
Sanchez-Echenique C.
et al.

Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II).

^,

⁹⁴

Vega A.
Martin-Ferrero M.A.
Del Canto F.
Alberca M.
Garcia V.
Munar A.
et al.

Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial.

. Of the 288 patients included in level I and II evidence studies, these two patients were the only two with serious adverse events. Gupta et al.

⁸⁹

Gupta P.K.
Chullikana A.
Rengasamy M.
Shetty N.
Pandey V.
Agarwal V.
et al.

Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel(R)): preclinical and clinical trial in osteoarthritis of the knee joint.

recorded only one therapy-related serious adverse event of a synovial effusion, which was managed with overnight observation. Pers et al.

⁹⁷

Pers Y.M.
Rackwitz L.
Ferreira R.
Pullig O.
Delfour C.
Barry F.
et al.

Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial.

reported unstable angina in 1 patient with risk factors of hypertension and hyperlipidemia.

Radiologic measures were taken in five of the level I and II evidence studies with either MRI or X-ray imaging

¹³

Jo C.H.
Lee Y.G.
Shin W.H.
Kim H.
Chai J.W.
Jeong E.C.
et al.

Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial.

^,

⁸⁷

Lamo-Espinosa J.M.
Mora G.
Blanco J.F.
Granero-Molto F.
Nunez-Cordoba J.M.
Sanchez-Echenique C.
et al.

Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II).

^,

⁹⁰

Jo C.H.
Chai J.W.
Jeong E.C.
Oh S.
Shin J.S.
Shim H.
et al.

Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a 2-year follow-up study.

^,

⁹¹

Koh Y.G.
Kwon O.R.
Kim Y.S.
Choi Y.J.

Comparative outcomes of open-wedge high tibial osteotomy with platelet-rich plasma alone or in combination with mesenchymal stem cell treatment: a prospective study.

^,

⁹⁴

Vega A.
Martin-Ferrero M.A.
Del Canto F.
Alberca M.
Garcia V.
Munar A.
et al.

Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial.

. With X-ray, no change in joint space width

⁸⁷

Lamo-Espinosa J.M.
Mora G.
Blanco J.F.
Granero-Molto F.
Nunez-Cordoba J.M.
Sanchez-Echenique C.
et al.

Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II).

or no difference in femorotibial angle and weight bearing lines was noted

⁹¹

Koh Y.G.
Kwon O.R.
Kim Y.S.
Choi Y.J.

Comparative outcomes of open-wedge high tibial osteotomy with platelet-rich plasma alone or in combination with mesenchymal stem cell treatment: a prospective study.

. MRIs have also shown promising outcomes with a decrease in joint damage in two studies

¹³

Jo C.H.
Lee Y.G.
Shin W.H.
Kim H.
Chai J.W.
Jeong E.C.
et al.

Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial.

^,

⁸⁷

Lamo-Espinosa J.M.
Mora G.
Blanco J.F.
Granero-Molto F.
Nunez-Cordoba J.M.
Sanchez-Echenique C.
et al.

Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II).

and a decreased poor cartilage index (PCI) in another

⁹⁴

Vega A.
Martin-Ferrero M.A.
Del Canto F.
Alberca M.
Garcia V.
Munar A.
et al.

Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial.

. There is, however, some question of sustainability of radiologic outcomes. Jo et al. (2017) found that although at 6 months cartilage defect size decreased and cartilage volume increased, the change plateaued by the two-year follow-up

⁹⁰

Jo C.H.
Chai J.W.
Jeong E.C.
Oh S.
Shin J.S.
Shim H.
et al.

Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a 2-year follow-up study.

.

Other measures less commonly used are noted in Table V including improvements in ICOAP

⁸⁹

Gupta P.K.
Chullikana A.
Rengasamy M.
Shetty N.
Pandey V.
Agarwal V.
et al.

Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel(R)): preclinical and clinical trial in osteoarthritis of the knee joint.

^,

⁹²

Shapiro S.A.
Kazmerchak S.E.
Heckman M.G.
Zubair A.C.
O'Connor M.I.

A prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis.

, joint flexion and extension measurements

⁸⁷

Lamo-Espinosa J.M.
Mora G.
Blanco J.F.
Granero-Molto F.
Nunez-Cordoba J.M.
Sanchez-Echenique C.
et al.

Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II).

, need for surgical intervention

⁹³

Turajane T.
Chaveewanakorn U.
Fongsarun W.
Aojanepong J.
Papadopoulos K.I.

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.

, Lequesne score

⁹⁴

Vega A.
Martin-Ferrero M.A.
Del Canto F.
Alberca M.
Garcia V.
Munar A.
et al.

Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial.

, SF-12/36 life quality questionnaire

⁹⁴

Vega A.
Martin-Ferrero M.A.
Del Canto F.
Alberca M.
Garcia V.
Munar A.
et al.

Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial.

^,

⁹⁷

Pers Y.M.
Rackwitz L.
Ferreira R.
Pullig O.
Delfour C.
Barry F.
et al.

Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial.

, -100-to-+100 pain relief score

⁸⁸

Centeno C.J.
Freeman M.D.

Percutaneous injection of autologous, culture-expanded mesenchymal stem cells into carpometacarpal hand joints: a case series with an untreated comparison group.

, KSS

¹³

Jo C.H.
Lee Y.G.
Shin W.H.
Kim H.
Chai J.W.
Jeong E.C.
et al.

Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial.

^,

⁹⁰

Jo C.H.
Chai J.W.
Jeong E.C.
Oh S.
Shin J.S.
Shim H.
et al.

Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a 2-year follow-up study.

, KOOS

⁹⁰

Jo C.H.
Chai J.W.
Jeong E.C.
Oh S.
Shin J.S.
Shim H.
et al.

Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a 2-year follow-up study.

^,

⁹¹

Koh Y.G.
Kwon O.R.
Kim Y.S.
Choi Y.J.

Comparative outcomes of open-wedge high tibial osteotomy with platelet-rich plasma alone or in combination with mesenchymal stem cell treatment: a prospective study.

^,

⁹⁷

Pers Y.M.
Rackwitz L.
Ferreira R.
Pullig O.
Delfour C.
Barry F.
et al.

Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial.

, Lysholm score

³⁰

Nguyen P.D.
Tran T.D.
Nguyen H.T.
Vu H.T.
Le P.T.
Phan N.L.
et al.

Comparative clinical observation of arthroscopic microfracture in the presence and absence of a stromal vascular fraction injection for osteoarthritis.

^,

⁹¹

Koh Y.G.
Kwon O.R.
Kim Y.S.
Choi Y.J.

Comparative outcomes of open-wedge high tibial osteotomy with platelet-rich plasma alone or in combination with mesenchymal stem cell treatment: a prospective study.

^,

⁹⁶

Wong K.L.
Lee K.B.
Tai B.C.
Law P.
Lee E.H.
Hui J.H.

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.

, Kanamiya grading

⁹¹

Koh Y.G.
Kwon O.R.
Kim Y.S.
Choi Y.J.

Comparative outcomes of open-wedge high tibial osteotomy with platelet-rich plasma alone or in combination with mesenchymal stem cell treatment: a prospective study.

, Modified Outerbridge classification

³⁰

Nguyen P.D.
Tran T.D.
Nguyen H.T.
Vu H.T.
Le P.T.
Phan N.L.
et al.

Comparative clinical observation of arthroscopic microfracture in the presence and absence of a stromal vascular fraction injection for osteoarthritis.

, activity level

⁹²

Shapiro S.A.
Kazmerchak S.E.
Heckman M.G.
Zubair A.C.
O'Connor M.I.

A prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis.

Crossref

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