Stem cell therapy in humans

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Osteoarthritis and Stem Cell Therapy in Humans: A Systematic Review

David S. Jevotovsky, BA, Allyson R. Alfonso, BS, BA, Thomas A. Einhorn, MD, Ernest S. Chiu, MD

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DOI: Reference:

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Received Date: Revised Date: Accepted Date:

S1063-4584(18)31080-X

10.1016/j.joca.2018.02.906

YJOCA 4193

Osteoarthritis and Cartilage

24 July 2017
21 January 2018 27 February 2018

Please cite this article as: Jevotovsky DS, Alfonso AR, Einhorn TA, Chiu ES, Osteoarthritis and Stem Cell Therapy in Humans: A Systematic Review, Osteoarthritis and Cartilage (2018), doi: 10.1016/ j.joca.2018.02.906.

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Osteoarthritis and Stem Cell Therapy in Humans: A Systematic Review

1 Authors: David S. Jevotovsky, BA*; Allyson R. Alfonso, BS, BA*; Thomas A. Einhorn, MD ;

2 Ernest S. Chiu, MD

Department of Plastic Surgery, NYU Langone Health, New York, NY *MD if delay in publication

Correspondence should be addressed to Ernest S. Chiu, MD (ernest_chiu@nyumc.org) or David S. Jevotovsky, BA (david.jevotovsky@nyumc.org)

Department of Orthopaedic Surgery, NYU Langone Health, New York, NY

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Abstract:

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:

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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.

Key words:

Osteoarthritis; stem cell therapy; mesenchymal stem cells; level of evidence; systematic review

Running headline:

Osteoarthritis and Stem Cell Therapy

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. 1 Introduction

. 2 Osteoarthritis (OA) is the most common joint disorder in the world and the most common

. 3 arthritis in the United States.1, 2 While worldwide prevalences of knee and hip OA are 3.8% and

. 4 0.85% respectively, this burden is likely underestimated.3

. 5 OA is the common end-point of many different pathologies. As such, its etiology is

. 6 varied, involving both intrinsic joint and extrinsic environmental factors. Age, gender,

. 7 menopause, genetics, nutrition and bone density often lead to increased susceptibility to OA.

. 8 These systemic factors, in addition to mechanical factors such as weight/body mass index, injury,

. 9 surgery, and deformity help determine the location and severity of an individual’s OA.1

. 10 Additionally, elevated inflammatory cytokines such as IL-1β and TNFα have recently been

. 11 implicated in OA’s pathogenesis.4

. 12 Existing treatments for OA are largely unsatisfactory. Pharmacologic management

. 13 includes acetaminophen, aspirin and oral non-steroidal anti-inflammatory drugs (NSAIDs).7, 8

. 14 Other options include capsaicin, duloxetine, topical NSAIDs and intra-articular corticosteroid

. 15 injections.5-7,These drugs are recommended secondarily to patient education, strengthening

. 16 exercises, and weight loss. Physical and occupational therapy have also demonstrated beneficial

. 17 effects.7, 8

. 18 These conservative treatments may be sufficient for early management, but their role in

. 19 modifying underlying structural abnormalities is limited. The OA Research Society International

. 20 suggests patients consider surgical interventions if daily pain persists for months and

. 21 conservative management has failed.8 Total joint replacements have thus become important in

. 22 the management of severe OA. In elderly populations, the prevalence of joint replacements due

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. 23 to OA is 13.6%.9 However, ongoing research aims to develop less invasive procedures for

. 24 management.

. 25 Less invasive procedures such as intra-articular injections of hyaluronic acid (HA),

. 26 platelet rich plasma (PRP), hypertonic dextrose prolotherapy and anabolic cartilaginous agents

. 27 are being studied as potential therapies.10-12 Intra-articular injection of mesenchymal stem cells

. 28 (MSCs) is an increasingly common adjuvant therapy that has shown promising results. A 2014

. 29 proof-of-concept trial demonstrated that intra-articular injection of MSCs into OA knees

. 30 improved function and pain without adverse events.13 Regeneration of hyaline-like articular

. 31 cartilage was noted.13 Critics, however, are skeptical of the quality of evidence and cost of cell-

. 32 based therapies.14

. 33 To date, few MSC-related adverse events have been noted.13 In a systematic review of the

. 34 safety of intra-articular therapy, 844 procedures (mean follow-up 21 months) were analyzed to

. 35 find only four serious adverse events: one infection post-bone marrow aspiration that resolved

. 36 with antibiotics, one pulmonary embolus two weeks after aspiration, and two adverse events

. 37 reported as unrelated to the therapy. Other sequelae included pain, swelling and dehydration after

. 38 aspiration.15 A more recent assessment of adverse events of autologous stem cell therapies

. 39 found they primarily included post-procedural pain or pain due to progressive degenerative joint

. 40 disease in under 4% of the population..16

. 41 The International Society for Cellular Therapy developed criteria to define MSCs as

. 42 plastic-adherent in culture conditions expressing CD105, CD73, and CD90, lacking expression

. 43 of CD45, CD34, CD14 or CD11b, CD79alpha or CD19, and HLA-DR surface molecules, and

. 44 possessing tri-lineage differentiation into osteoblasts, adipocytes and chondroblasts. 17, 18

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. 45 However, the term MSC is not always used in the literature with this definition in mind.

. 46 Evidence supporting the immunomodulatory role of MSCs suggests the term “stem cell” is a

. 47 misnomer and the name be changed to medicinal signaling cells,19 though this change has yet to

. 48 be reflected in the literature. The immunomodulatory properties of MSCs, however, have been

. 49 postulated to have the capacity to play a role in manipulation of the disease process.These

. 50 properties include anti-inflammatory, anti-apoptotive, anti-fibrotic, angiogenic, mitogenic and

. 51 wound-healing paracrine activity.20, 21

. 52 MSCs can be harvested from several sites including bone marrow (BMSCs), adipose

. 53 tissue (ADSCs), synovium (SDSCs) or peripheral blood (PBSCs).18 BMSCs and ADSCs have

. 54 received considerable attention due to their ease of extraction.22 Once removed, typically from

. 55 the iliac crest, BMSCs can be expanded in culture and induced to various stages of

. 56 differentiation.22, 23 Adipose tissue is abundant, making ADSC procurement easy and minimally

. 57 invasive.24 ADSCs can differentiate into fat, bone or cartilage.25 These cells are harvested from

. 58 infra-patellar fat pads or subcutaneous sites such as the buttocks.26 There is debate regarding the

. 59 differences between BMSCs and ADSCs in terms of cell yield, growth kinetics, and

. 60 differentiation capacity.24, 27 However, both animal and human models have shown positive

. 61 results for OA treatment with these MSC types.28-30 SDSCs, often harvested from the knee, are

. 62 recognized for their differentiation potential and high cell yield. 31 PBSCs are collected via

. 63 minimally invasive apheresis but are used less frequently.32 When freshly collected, PBSCs do

. 64 not display MSC markers unless in hypoxic conditions33 or after subcutaneous administration of

. 65 human granulocyte colony stimulating factor prior to blood draw.34

. 66 The above MSCs can be isolated, culture-expanded and subsequently injected into joints.

. 67 Other intra-articular formulations with one-step harvest and injection procedures are becoming

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. 68 popular, including injection of bone marrow aspirate concentrate (BMAC) containing BMSCs,

. 69 stromal vascular fraction (SVF) isolated from lipoaspirate containing ADSCs, and

. 70 microfragmented adipose tissue, a non-enzymatic approach to isolating the stromal vascular

. 71 niche with ADSCs. SVF is isolated via liposuction, followed by collagenase digestion,

. 72 centrifugation, and dilution.25, 35, 36 BMAC contains a mixture of platelets, red and white blood

. 73 cells, and hematopoietic and non-hematopoietic precursors. The term refers to the mixture of

. 74 marrow elements and MSCs, but, after processing, only 0.001% to 0.01% of the cells are

. 75 MSCs.37The SVF product contains MSCs, pericytes, fibroblasts, monocytes and macrophages,

. 76 with 500,000 to 2,00,000 cells per gram of which 1 to 10% are considered ADSCs.35, 36

. 77 Microfragmented adipose tissue is obtained by harvesting lipoaspirate and washing off residues

. 78 while adipose cluster dimensions are gradually reduced. Initial analysis has shown it contains

. 79 preserved stromal vascular architecture with pericytes and MSCs.38

. 80 Although MSC therapy has been used to treat articular cartilage repair for years, few

. 81 clinical studies provide satisfactory levels of evidence to address the quality of available

. 82 information. The Journal of Bone and Joint Surgery’s (JBJS) Levels of Evidence rating scale

. 83 defines parameters to help authors make level of evidence evaluations (level I, randomized

. 84 controlled trial; level II, prospective cohort study or observational study with dramatic effect;

. 85 level III, retrospective cohort study or case-control study; level IV, case series; level V,

. 86 mechanism-based reasoning).39 These parameters help inform physician’s clinical decisions.

. 87 To our knowledge, there has been no systematic review which analyzes the effect of

. 88 study quality and procedural specifics of both autologous and allogeneic MSC therapy for the

. 89 treatment of OA. The aims of this investigation are to provide an analysis of the literature

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. 90 regarding the use of MSC therapy for OA treatment, to assess the quality of evidence, and to

. 91 propose next steps for further investigation.

. 92 Methods

. 93 Search strategy

. 94 This review was conducted according to Preferred Reporting Items for Systematic

. 95 Reviews and Meta-analysis (PRISMA) guidelines.40 A literature search identified all articles

. 96 involving stem cell therapy to treat osteoarthitis. PubMed, CINAHL, EMBASE and Cochrane

. 97 Central Register of Controlled Trials were searched using “osteoarthritis” and “stem cell” MeSH

. 98 terms presented in further detail in the appendix. Computer de-duplication was performed. The

. 99 search was finalized in December 2017. Manual review of the references of selected articles was

. 100 also completed to add studies that were originally missed.

. 101 Study selection

. 102 Two reviewers (DJ and AA) independently evaluated studies. Third and fourth reviewers

. 103 (TE and EC) resolved any discrepancies for inclusion. After identifying the relevant studies

. 104 through abstract information, studies were included after full-text evaluation. Inclusion criteria

. 105 was any clinical study that used stem cells to treat osteoarthritis in humans. Outcome measures

. 106 varied amongst articles. These measures included safety analyzed by the nature of adverse

. 107 events, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the

. 108 Visual Analogue Scale (VAS) for pain, radiographic MRI or X-ray scores, as well as several

. 109 others. Articles from any country were acceptable but limited to those published in the English

. 110 language. Exclusion criteria were articles that did not use MSCs to directly treat OA patients,

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. 111 that were reviews, conference submissions/abstracts only or letters to the editor, that studied

. 112 stem cells in vitro, that studied isolated, focal chondral defects not associated with OA, and that

. 113 presented their research in a language other than English.

. 114 Data extraction and assessment of study quality

. 115 Authors (DJ and AA) independently extracted data using a template data extraction sheet,

. 116 with third and fourth researchers (TE and EC) serving as tiebreakers if consensus was not

. 117 achieved. Information gathered included study characteristics, patient demographics and

. 118 outcomes. Primary outcome was the improvement, or lack thereof, in the patients’ OA. Studies

. 119 were rated on methodological quality according to The JBJS Levels of Evidence rating

. 120 scale.39 Risk of bias assessment was completed to evaluate each study’s internal validity using

. 121 Cochrane’s Risk of Bias scale for randomized trials (RoB2.0)41 and Risk of Bias In Non-

. 122 randomised Studies – of Intervention (ROBINS-I) tool.42

. 123 Analysis

. 124 Because of overall study heterogeneity and lack of adequate control groups, a formal

. 125 statistical meta-analysis was attempted but not performed; however, pooled rates of several

. 126 collected measures were calculated with the available data using Microsoft Excel when

. 127 applicable.

. 128 Results

. 129 Literature Search

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. 130 The initial search of the three databases yielded a total of 3,416 articles. Nine articles

. 131 were identified through other sources. Duplicates were removed and 3,172 articles remained. Of

. 132 these articles, 381 were selected as relevant to the application of stem cell therapy for OA

. 133 treatment. Of those articles, 61 were chosen to be discussed in this review due to their clinical

. 134 nature. The PRISMA flow diagram can be visualized in Figure 1. According to Marx, Wilson

. 135 and Swiontkowski (2015), five studies classified as level I evidence, nine as level II, seven as

. 136 level III, thirty-five as level IV, and five as level V.

. 137 Levels I-V (all clinical studies): Study Characteristics and Intervention Details

. 138 In total, the 61 studies enrolled 2,390 OA patients to be treated with MSC therapy. Table

. 139 1 gives an overview of study characteristics, while Table 213, 29, 30, 43-100 provides individual study

. 140 details organized by level of evidence. Of the total study population, 2,662 joints were treated

. 141 and 46% were female (N=1095). OA sites included knee (51 studies), hand (2 studies), ankle (3

. 142 studies), shoulder (1 study), hip (2 studies) or multiple joints (2 studies with knee, hip and ankle).

. 143 In the 61 clinical studies, MSC type varied between ADSCs (29 studies), BMSCs (30

. 144 studies), and PBSCs (3 studies), and allogeneic umbilical cord-derived MSCs (1 study), taking

. 145 into account that two studies used both ADSCs and BMSCs.64,89 Among these studies, the

. 146 processing and injected/implanted form also differed. ADSCs were either culture-expanded

. 147 (n=3), within SVF (n=24) or microfragmented adipose tissue (n=2). BMSCs were either culture-

. 148 expanded (n=18), within BMAC (n=10), or allogenic (n=2). Three studies used PBSCs and one

. 149 study used allogeneic umbilical cord-derived MSCs. Several adjuvants were injected/implanted

. 150 with the MSCs, including PRP (n=20), platelet lysate (n=8), and hyaluronic acid (n=10). The

. 151 median follow-up time was 12 months with a range of 3 to 84 months.

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. 152 To better understand the quality of the literature pertaining to MSCs as OA therapy, the

. 153 fourteen Level I and Level II articles were analyzed further.

. 154 Levels I-II Only: Study Characteristics

. 155 Of the fourteen Level I and Level II evidence articles, 288 total patients were studied.

. 156 Sixty-three percent of these patients were female (n=181). Thirteen studies treated knee OA and

. 157 1 treated hand OA. Study characteristics of the Level I and II studies can be found in Table 2.

. 158 As depicted in Table 3, the RoB 2.0 and ROBINS-I risk of bias quality assessment yielded five

. 159 studies at low risk of bias, seven at moderate/some concerns risk, and two at high risk.

. 160 Levels I-II Only: Intervention Details

. 161 In the Levels I and II cohort, 288 patients received MSC therapy. MSC regimen varied; a

. 162 summary of the intervention details can be found in Table 4. Eight studies used BMSCs collected

. 163 from the iliac crest. Of these, four were culture-expanded, 2 were BMAC and 2 were allogeneic.

. 164 Five studies used ADSCs with four derived from abdominal fat and one from the buttocks. Of

. 165 these five studies, 3 were culture-expanded injecting a range of 2 x 106 to 100 x 106 ADSCs and

. 166 2 were from SVF injecting a magnitude of 107 SVF cells with one study estimating this as 4.11 x

. 167 106 ADSCs.88 Turajane, Chaveewanakown, Fongsarun, Aojanepong and Papadopoulos (2017)

. 168 was the only one of these studies to inject 3ml PBSCs containing a range of 1.095-1.276 x 106

. 169 total nucleated cells. This study employed three injections and compared groups that received

. 170 microdriling, PBSC, growth factor addition, and HA (group 1) versus PBSC, PRP, HA (group 2)

. 171 versus HA alone (group 3). The mean follow-up length of time for all studies was 14 ± 7 mo

. 172 (Range 6 to 24).107

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. 173 Outcome Assessments

. 174 All 61 clinical studies reported some level of improvement of OA symptoms from

. 175 baseline in the MSC therapy group. Main findings of outcome assessments in level I and II

. 176 studies can be found in Table 5.13, 29, 30, 90-100 Although there was overlap between outcome

. 177 measures between included Level I and II articles, no meta-analysis was performed due to the

. 178 diversity of metrics and outcomes. The most common measures were VAS (n=10), WOMAC

. 179 (n=9), safety (n=6) and radiologic evidence (n=5).

. 180 Of the ten level I and II evidence studies that measured VAS for pain, patients in all of the

. 181 studies exhibited VAS score improvements.29, 30, 90-95, 97, 100 In four of these studies, VAS

. 182 improved compared to placebo.29, 30, 90, 94, 97 Lamo-Espinosa et al.90 found the high-dose BMSC-

. 183 treated patients’ VAS improved significantly (p<0.01) compared to placebo of HA alone. Garay-

. 184 Mendoza et al.29 found VAS improvements at 1 week (p=0.0003), 1 month (p<0.0001), and 6

. 185 months (p<0.0001). Notably, the BMSC-treated group VAS pain score (0.92 ± 1.29) was lower

. 186 compared to the daily acetaminophen placebo group (4.64 ± 2.43). Vega et al. 97 found BMSC-

. 187 treated patients demonstrated significant VAS improvement at 6 months, whereas placebo HA-

. 188 treated patients did not significantly improve until 12 months. Similarly, Koh et al.94 found that

. 189 both ADSC-treated patients and PRP-placebo patients improved their VAS scores at 6 and 12

. 190 months, but the ADSC-treated group demonstrated a greater VAS improvement (10.2 ± 5.7) than

. 191 the placebo group (16.2 ± 4.6). Additionally, Nguyen et al. 30 found the ADSC-treated group

. 192 (3.47 ± 0.74) improved significantly compared to the microfracture placebo group (2.08 ± 1.08).

. 193 The remaining studies measuring VAS exhibited improvement upon follow-up but the

. 194 improvement was either not statistically significant,92 not compared to the placebo,91 or there

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. 195 was no placebo to compare to.93, 100 One study showed VAS improvement with MSC treatment

. 196 but no significance when compared to saline injection placebo (p>0.09).95

. 197 All level I and II studies that measured WOMAC also saw improvements upon follow-up.13, 29, 30,

. 198 90, 92, 93, 96, 97 Lamo-Espinosa et al.90 showed improved WOMAC scores in high-dose BMSC-

. 199 treated patients than in the HA placebo group (p<0.01). Garay-Mendoza et al.29 reported similar

. 200 improvement compared to acetaminophen placebo.Turajane et al.96 also found significantly

. 201 better WOMAC scores in PBSC-treated groups (WOMAC = 52 or 75) compared to the HA-

. 202 placebo group (WOMAC = 126.8) at 12 months (p<0.001). Two studies recorded improved

. 203 WOMAC scores, but not when compared to placebo groups,92, 97 and three studies exhibited

. 204 improved WOMAC but lacked a placebo to compare to.13, 30, 93 In one study, Garay-Mendoza et

. 205 al.29 demonstrated that BMSC treatment may lead to higher WOMAC scores (91.27 ± 9.45)

. 206 compared to acetaminophen placebo (72.35 ± 17.37).

. 207 Few serious adverse events were found in level I and II evidence studies that measured safety.13,

. 208 29, 90, 92, 97, 100 Four studies found no serious events as a consequence to MSC-treatment, but

. 209 patients noted mild pain and swelling post-treatment that was treated with ibuprofen.13, 29, 90, 97 Of

. 210 the 288 patients included in level I and II evidence studies, these two patients were the only two

. 211 with serious adverse events. Gupta et al.92 recorded only one therapy-related serious adverse

. 212 event of a a synovial effusion, which was managed with overnight observation. Pers et al.100

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

. 214 Radiologic measures were taken in five of the level I and II evidence studies with either MRI or

. 215 X-ray imaging.13, 90, 93, 94, 97 With X-ray, no change in joint space width90 or no difference in

. 216 femorotibial angle and weight bearing lines was noted.94 MRIs have also shown promising

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. 217 outcomes with a decrease in joint damage in two studies13, 90 and a decreased poor cartilage

. 218 index (PCI) in another.97 There is, however, some question of sustainability of radiologic

. 219 outcomes. Jo et al (2017) found that although at 6 months cartilage defect size decreased and

. 220 cartilage volume increased, the change plateaued by the two-year follow-up.93

. 221 Other measures less commonly used are noted in table 5 including improvements in ICOAP,92, 95

. 222 joint flexion and extension measurements,90 need for surgical intervention,96 Lequesne score,97

. 223 SF-12/36 life quality questionnaire,97, 100 -100-to-+100 pain relief score,91 KSS,13, 93 KOOS,93, 94,

. 224 100 Lysholm score,30, 94, 99 Kanamiya grading,94 Modified Outerbridge classification,30 activity

. 225 level,95 HSS Knee Rating Scale,98 and second look arthroscopy and histology.98

. 226 Discussion

. 227 Stem cell therapy appears to alleviate the symptoms of osteoarthritis and potentially halt

. 228 cartilage damage. Although studies detailing the therapeutic effect of MSCs in osteoarthritic

. 229 patients are limited in number and quality, the majority of available literature has reported

. 230 positive results. The studies, however, are inconsistent in their methodology and few studies are

. 231 levels I or II evidence. Over half (57%) of evidence available is level IV evidence which consists

. 232 of therapeutic case series without comparative groups.39 Nonetheless, analysis of the articles’

. 233 results suggest an association between MSC therapy and OA symptomatic and radiologic

. 234 improvement. There has been some conflicting evidence, however, in the longterm maintenance

. 235 of positive results. In a two-year follow-up, Jo et al.79 found that although WOMAC, VAS, KSS

. 236 and KOOS improved from baseline, these scores plateaued or decreased after one year. To the

. 237 contrary, Nguyen et al. 44 looked at WOMAC, Lysholm score, and VAS and found that both

. 238 treatment and placebo groups significantly improved from baseline (p<0.05), but it was not until

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. 239 18 months that the treated group had significantly improved scores compared to placebo

. 240 (p<0.05). This supports the need for studies that assess longer term clinical outcomes in order to

. 241 better understand the intervention’s sustainability. This also draws attention to the need for

. 242 protocol consistency since it is difficult to formulate conclusions from these longterm studies

. 243 when different forms of MSC administration are used, as demonstrated by these examples,

. 244 respectively.44, 79

. 245 MSC therapy caused few adverse effects in studies that investigated treatment safety.

. 246 Two serious adverse events were recorded in the levels I and II evidence including a synovial

. 247 effusion requiring overnight observation92 and unstable angina in a patient with multiple risk

. 248 factors three months after injection.92 Other adverse events recorded included pain and swelling.

. 249 Vega et al.97 found 50-60% of all patients, both treatment and control group, experienced

. 250 inflammation and swelling post-injection procedure. This highlights the possibility of adverse

. 251 events being due to injections in general, versus the stem cells themselves. As previously

. 252 mentioned, this is supported by systematic reviews for the safety of therapeutic uses of

. 253 mesenchymal stem cells. The most common adverse events noted in these studies have been pain

. 254 and swelling15, 16 with several studies rejecting a previous concern for increased tumor risk.16, 76,
85

. 256 The methodology of the included studies was widely variable. This suggests that studies

. 257 have not been replicated to validate results, which limited our ability to conduct meta-analysis.

. 258 There is no consensus as to which MSC type is most effective at treating OA. More recently,

. 259 one-step preparation of MSC-containing product including SVF, BMAC or microfragmented

. 260 adipose tissue adds to this variability. Even within the levels I and II evidence articles, there was

. 261 no dominant stem cell type; the research spanned ADSCs (5 study), BMSCs (8 studies), and

255

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. 262 PBSCs (1 study), and, within each MSC type, procedural variability remains. Amongst the

. 263 levels I and II evidence, three studies used radiographic guidance,91, 95, 100one used arthroscopic

. 264 guidance,88 one was implanted in an open procedure,98 while nine reported neither. Three

. 265 studies96, 98, 99 were completed in conjunction with a surgical procedure. There is also variability

. 266 in adjuvants, but the most common used are PRP (n=20), platelet lysate (n=8), and hyaluronic

. 267 acid (n=10).

. 268 Besides the lack of consistent methodologies, this study elucidates the scarcity of quality

. 269 evidence. The majority (57%) of included clinical studies were level IV case series, an additional

. 270 11% were level III retrospective cohort studies and 8% were level V single patient case reports.

. 271 Furthermore, risk of bias is a concern amongst the level II evidence articles (15% of included

. 272 studies), with all at moderate/some concerns or high risk of bias, indicating the potential for

. 273 underestimation or overestimation of results. These data demonstrate the need for higher quality

. 274 evidence regarding MSC treatment for OA. The literature needs more level II prospective cohort

. 275 studies designed to minimize risk of bias and, importantly, more level I randomized controlled

. 276 trials to effectively evaluate the MSC treatment. All current level I evidence articles were

. 277 categorized as low risk of bias, which is promising for future publication of well-designed

. 278 studies, though consensus must still be reached on proper methodology.

. 279 There are several limitations to this study. Many studies in foreign languages were

. 280 excluded due to our inability to analyze them. Another limitation lies in our choice of evidence

. 281 levels and risk of bias. Marx, Wilson, Swiontkowski (2015) allows authors to use their

. 282 professional judgment to grade levels of evidence,39as do the tools for assessing risk of bias.59, 60

. 283 Thus, there is flexibility in selecting levels of evidence and risk of bias, though the authors

. 284 collaborated to arrive at conclusions. Additionally, we recognize the need for consistency

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. 285 between studies, including but not limited to MSC type/implanted or injected material, number

. 286 of cells injected/implanted, use of biologic adjuvants and outcome measures. With this, we also

. 287 recognize that the reported outcome measures exist without a true understanding of the

. 288 mechnanism of action of MSCs. This makes it difficult for us to truly understand results. For

. 289 example, after finding improvement in treatment groups using each patient’s contralateral knee

. 290 as a control, Shapiro et al.105 speculated several explanations for their results including the

. 291 possibility of systemically mediated effects of BMAC, paracrine signaling mechanisms,

. 292 chondrogenic potential and even the interaction of other cells in the concentrate. The answer was

. 293 not found and needs further study. We are therefore unable to propose guidelines of stem cell

. 294 therapy extraction and injection methods based on the available evidence. Lastly, we recognize

. 295 that active stem cell therapy clinical trials found through clinicaltrials.gov were not included in

. 296 our analysis of the literature. Mamidi et al.101 reviewed the obstacles faced by clinical trials and

. 297 found 40 clinical trials registered in 19 different countries. These studies will hopefully be a

. 298 source of new and more reliable evidence.

. 299 The Food and Drug Administration (FDA) regulates the use of adult stem cells. In 2006,

. 300 the FDA adopted 21 CFR 1271, which modified its jurisdiction over human cells and tissues to

. 301 include any “transfer into a human recipient.” 102 Previously, the code was specified transfer

. 302 “into another human,” excluding autologous cells.103, 104 Since then, cells that are more than

. 303 “minimally manipulated,” even if they are intended for autologous use, are subject to similar

. 304 regulations as manufactured drugs.103, 104 Therefore, higher quality evidence is not only needed to

. 305 convince physicians, but the FDA as well, of the safety and efficacy of MSCs. High level,

. 306 quality evidence for MSC therapy would allow the FDA and physicians to more confidently

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. 307 provide patients with alternative, minimally invasive treatment options that may significantly

. 308 slow disease progression.

. 309 The need to further investigate MSC therapy for OA comes from the quality of the

. 310 existing treatment options. OA treatment thus far relies on conservative management and

. 311 invasive joint replacement surgeries.5-8 Stem cell therapy is a rapidly evolving treatment for

. 312 osteoarthritis that has been used despite proper evidence to support its application. Few high

. 313 level of evidence articles have been published with respect to this matter. Although MSC safety

. 314 has been shown, the literature has no cohesive picture regarding the proper collection and

. 315 administration of stem cells. We have reported a general link between MSC therapy and OA

. 316 symptomatic improvement , but the data is limited by study quality. A well-designed randomized

. 317 controlled trial with reproducible methodology is needed to further evaluate how different

. 318 derivatives of MSCs such as BMSCs, ASCs, and PBSCs affect OA as well as MSC-containing

. 319 products such as SVF or BMAC.

. 320 Acknowledgements:

. 321 The authors would like to thank Richard McGowan and Joseph Nicholson for their

. 322 assistance in the collection of relevant articles and David Gothard, MS for his help with

. 323 statistical analysis.

. 324 Contributions:

. 325 David S. Jevotovsky, BA: This author was responsible for the design of the study as well as

. 326 acquisition, analysis and interpretation of data. He drafted, revised, and was part of the final

. 327 approval process.

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. 328 Allyson R. Alfonso, BS, BA: This author was responsible for the conception of the study,

. 329 elaboration of study design, acquisition of data, analysis and interpretation of the data. She

. 330 revised the article and was part of the final approval process.

. 331 Thomas A Einhorn, MD: This author was part of the conception and design of the study. He

. 332 helped revise the article for important intellectual content and was part of the final approval

. 333 process.

. 334 Ernest S. Chiu, MD: This author is the principal investigator for this work. He was responsible

. 335 for design of study as well as analysis and interpretation of data. He also contributed to revision

. 336 of the manuscript and final approval.

. 337 Role of the funding source:

. 338 The authors have no funding source to declare. No other parties other than those listed as authors

. 339 or under acknowledgements influenced the study design, collection, analysis and interpretation

. 340 of data, writing of manuscript, or decision to submit the manuscript for publication.

. 341 Competing Interest Statement:

. 342 Dr. Einhorn reports personal fees from Agnovos, personal fees from Pluristem, personal fees

. 343 from Harvest Technologies, outside the submitted work. In addition, Dr. Einhorn has a patent

. 344 MyDigitalRx pending and is an investor with HealthpointCapital, a private equity firm in the

. 345 orthopaedic space. The other authors have no conflicts of interests to report.

. 346 References

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682

ACCEPTED MANUSCRIPT

Table 1. Overview of the included clinical studies

N* (male/female)

OA Site

MSC Type**

Levels of Evidence***

2,390 (1095/1315)****

Ankle 3

Hand 2 Shoulder 1 Hip 2

Multiple 2 Knee/Hip/Ankle

ADSC 29

BMSC 30

SVF 24 Micro 2

CE 18

BMAC 10

Allog 2

II 9 III 7

IV 35

Knee51 CE3I5

PBSC 3 Allog

hUCB- 1 MSCs

ADSC = adipose-derived stem cell; BMSC = bone-marrow stem cell; MSC = mesenchymal stem cell; OA = osteoarthritis; PBSC = peripheral blood stem cell.
*Number of patients treated with stem cell therapy

58, 60 ** 2 studies used both SVF/ADSC and BMAC/BMSC

***Levels of evidence according to Marx, Wilson, & Swiontkowski (2015)
****Based on total number of joints of those studies that reported gender (6 studies did not report gender by joint)
CE: culture-expanded; Allog: allogeneic; Micro: microfragmented; hUCB-MSCs: human umbilical cord blood-derived mesenchymal stem cells

74, 109, 116, 98, 111, 112

ACCEPTED MANUSCRIPT

Table 2. Study characteristics of the included clinical studies grouped by level of evidence

First Author (Date of Publication) Garay-Mendoza

Country of Origin

Level of 57

N* (Male/Female)

OA Site

MSC Source/ Type

Biologic Adjuvant

Outcome Measures

Follow-Up Length of Time

(2017)

Mexico

30 (7/23)

Knee

BMAC/ BMSC

Outpatient
SQ G-CSF x 3 days PLASMALYTE-A Pre: Hydrocortisone and pheniramine maleate
Post: Hyaluronic acid

VAS WOMAC

6 mo

Gupta (2016)

India

40 (12/28)

Knee

Allogeneic culture- expanded BMSC

VAS for pain ICOAP WOMAC WORMS – knee

12 mo

Lamo-Espinosa

Spain

20 (12/8)

Knee

Culture- expanded BMSC

Hyaluronic acid

VAS
WOMAC
RoM
X-ray knee joint space width WORMS
Need for surgical intervention at 12mo WOMAC
VAS
WOMAC
Lequesne functional index SF-12 life quality questionnaire MRI T2 mapping, PCI

12 mo

(2016)

Turajane (2017)

Thailand

40 (13/27)

Knee

PBSC

Hyaluronic acid, GFA (PRP, hG-CSF)

12 mo

Vega (2015)

Spain

15 (6/9)

Knee

Allogeneic culture- expanded BMSC

n/a

12 mo

Centeno (2014)

Denmark, Sweden, USA

6 (4/2)

Hand

Culture- expanded BMSC

Platelet lysate

Percent pain relief
Modified VAS
Strength, ROM
WOMAC
Safety
Secondary: VAS, KSS, radiographic, histologic evaluation
WOMAC
KSS
KOOS
VAS for pain
MRI evaluation including cartilage defect size KOOS
Lysholm score
X-ray (femorotibial angle, weight-bearing line) Second-look arthroscopy evaluation of cartilage – Kanamiya grading system
WOMAC
Lysolm score
VAS for pain
Modified Outerbridge classification
VAS for pain
WOMAC
Patient Global Assessment
KOOS
SAS
SF-36
OARSI/OMERACT Responders
VAS for pain
ICOAP
WOMAC
KOOS
Activity level

12 mo

Jo (2014)

Korea

18 (3/15)

Knee

Culture- expanded ADSC

n/a

6 mo

Jo (2017)

Korea

18 (3/15)

Knee

Culture- expanded ADSC

n/a

24 mo Follow-up

Koh (2014)94

Korea

21 (5/16)

Knee

SVF/ ADSC

PRP

Mean 24.2± 4.7 mo

Nguyen (2016)

Vietnam

15 (3/12)

Knee

SVF/ ADSC

PRP

18 mo

Pers (2016)

100

France, Germany

18 (8/10)

Knee

Culture- expanded ADSC

n/a

6 mo

Shapiro (2017)

USA

25 (7/18)

Knee

BMAC/ BMSC

Platelet-poor bone marrow plasma

6 mo

Wakitani (2002)

Japan

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)

Singapore

28 (15/13)

Knee

Culture- expanded BMSC

Hyaluronic acid

Tegner activity score Lysholm score IKDC
ICRS MOCART

2 yrs

Centeno (2015)

USA

III

373 (283/126)

Knee

BMAC/ BMSC

PRP, Platelet lysate

NPS
LEFS
Subjective Improvement Rating Scale IKDC
NPS

Varied by outcome, at least 12 mo

Centeno (2014)

USA

III

681 (516/324)**

Knee

BMAC/BMSC

PRP,

12 mo

Evidence

ACCEPTED MANUSCRIPT

Jo (2014)

ACCEPTED MANUSCRIPT

Kim (2015)62 Kim (2016)63

Korea III

56 (22/32)**

Knee

SVF/ ADSC

Group 1: n/a Group 2: fibrin glue product

Mean 28.6± 3.9 mo (Range 24-34 mo)

Kim (2015)64

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

Kim (2016)65

Korea III

31 (15/16)

Ankle

SVF/ ADSC

n/a

VAS for pain
AOFAS
Radiological tibial ankle surface, tibial lateral surface and talar tilt angle
ICRS grade
Lysholm score
Tegner activity scale
VAS for pain

Mean 27.6± 5.0 mo Mean 16.4± 2.3 mo

Koh (2012)94 Ahmad (2014)

Korea III

25 (8/17)

Knee

SVF/ ADSC

PRP

(Range 12- 18 mo)

Bansal (2017)

India IV

10 (6/4)

Knee

SVF/ ADSC

PRP

2 yrs

Buda (2016)

Italy IV

56 (37/19)

Ankle

BMAC/ BMSC Culture- expanded BMSC

Autologous platelet- rich fibrin

36 mo

Centeno (2011)

USA IV

135 (93/42)

Knee

Platelet lysate or PRP

Likert scale for reported pain relief

Mean 11.3 mo

Centeno (2015)

USA IV

34 (27/7)

Shoulder

BMAC/ BMSC

PRP, Platelet lysate

DASH
NPS
Subjective Improvement Rating Scale VAS for pain
Walking time to pain
Number of stairs to pain
Time to gelling pain
RoM
Patellar crepitus
Swelling, Instability

At least 3 mo

Davatchi (2011)

Iran IV

4 (2/2)

Knee

Culture- expanded BMSC

Physiological serum

6 mo

Davatchi (2016)

Iran IV

4 (2/2)

Knee

Physiological serum

Same as Davatchi (2011)

Emadedin (2012)

Iran IV

6 (0/6)

Knee

Culture- expanded BMSC

n/a

VAS
WOMAC
Walking distance
Time to gelling
Patellar crepitus
RoM
MRI cartilage assessment VAS
WOMAC
HHS
FAOS
Walking distance
Lab studies
MRI analysis
VAS for pain
WOMAC
RoM
Timed up-and-go
MRI – observational
KOOS
Physical function tests: GUG, SCT RPE
VAS for pain dGEMRIC
IgG Glycans

12 mo

Emadedin (2015)

Iran IV

17(X/X)

Ankle (n=6) Hip (n=5) Knee (n=6)

Culture- expanded BMSC

n/a

30 mo

Fodor (2016)

USA IV

6 (1/7)**

Knee

SVF/ ADSC

n/a

1 yr

Gibbs (2015)

Australia IV

4 (2/2)

Knee

SVF/ ADSC

PRP, Moderate exercise program

12 mo

Hudetz (2017)

Croatia IV

17 (12/5)

Knee

Microfragment ed/ ADSC

n/a

12 mo

Egypt IV

10 (3/7)

Knee

PBSC

n/a

WOMAC
6MWD
MOAKS
WOMAC
6MWD
X-ray joint space width MRI articular cartilage thickness AOFAS
MOCART

12 mo

Korea III

26 (11/15)

Ankle

SVF/ ADSC

n/a

Mean 27.7± 2.4 mo (Range 24-34 mo)

ACCEPTED MANUSCRIPT

LEFS
Subjective Improvement Rating Scale IKDC
Tegner activity scale
ICRS grade
VAS for pain
AOFAS
Radiological talar tilt angle ICRS grade

± SVF/ADSC

Platelet lysate

Culture- expanded BMSC

7 Patient Global Assessment

5 yrs Follow-up Davatchi

(2011)

ACCEPTED MANUSCRIPT

Kim (2015)60 Kim (2016)61

Korea

IV 49 (26/29)**

Knee

SVF/ ADSC

Fibrin glue product

Mean 26.7± 3.6 mo (Range 24-36 mo)

Koh (2015)

Korea

IV 30 (5/25)

Knee

SVF/ ADSC

PRP

24 mo

Koh (2013)67

Korea

IV 18 (6/12)

Knee

SVF/ ADSC

PRP

Mean 24.3± 0.8 mo (Range 24- 26 mo)

Koh (2014)69

Korea

IV 56 (22/34)

Knee

SVF/ ADSC

n/a

Mean 26.7± 2.5 mo

Mardones (2017)

Chile

IV 10 (7/6)**

Hip

Culture- expanded BMSC

n/a

Range 16-40 mo

Murphy (2017)

Ireland

IV 13 (2/11)

Thumb – CMC joint

BMAC/ BMSC

Tisseel

12 mo

Oliver (2014)

USA

70 (21/49), 122 knees

Knee

BMAC/ BMSC + SVF/ADSC

n/a

180 days

Orozco (2013)

Spain

IV 12 (6/6)

Knee

Culture- expanded BMSC

n/a

12 mo

Orozco (2014)

Spain

IV 12 (6/6)

Knee

Culture- expanded BMSC

n/a

2 yrs Follow-up Orozco

Pak (2011)

Korea

IV 2 (0/2)

Knee

SVF/ ADSC

PRP, dexamethasone, hyaluronic acid

3 mo

Pak (2013)

Korea

IV 74 (X/X)

7) Knee (n = 74)

SVF/ ADSC

PRP, Hyaluronic acid

VAS for pain
MRI – assessed for tumor formation

At least 12 mo

Pak (2016)

Korea

IV 3 (1/2)

Knee

SVF/ ADSC

ECM, Hyaluronic acid, PRP

VAS
Functional Rating Index RoM
MRI cartilage assessment ICRS grade
VAS for pain
IKDC Histological findings WOMAC
MRI – ICRS-like classification VAS for pain
KOOS

18 wks

Park (2017)

Korea

IV 7 (2/5)

Knee

Allogeneic, culture-expanded hUCB-MSCs

Hyaluronic acid hydrogel

7 yrs

Pintat (2017)

France

IV 19 (10/9)

Patellofemoral

SVF/ ADSC

PRP

12 mo

Russo (2017)

Italy

IV 30 (21/9)

Microfragment
Knee n/a 12mo

Soler (2016)

Spain

IV 15 (6/9)

Culture- Knee expanded

n/a

12 mo

Turajane (2013)

Thailand Vietnam

IV 5 (1/4) IV 21 (X/X)

Knee PBSC Knee SVF/ ADSC

Hyaluronic acid, GFA (PRP, hG-CSF) PRP

6mo 8.5 mo

Bui (2014)

Korea

IV 20 (9/15)**

Knee

SVF/ ADSC

Fibrin glue product

Mean 27.9± 3.2 mo (Range 24-34 mo)

ACCEPTED MANUSCRIPT

IKDC score
Tegner activity scale
Overall surgery satisfaction
IKDC
Tegner activity scale
MOAKS
MOCART
KOOS
Lysholm score
VAS
Second-look arthroscopy evaluation of cartilage WOMAC
Lysholm score
VAS for pain
WORMS
IKDC
Tegner activity scale
Patient satisfaction
Second-look arthroscopy – ICRS
VAS
WOMAC
HHS
VAIL hip score
Tönnis Classification of Osteoarthritis
VAS
RoM
Kapandji opposition score
Strength (pinch test)
DASH
Grind test
KOOS
Adverse events
VAS
WOMAC
Lequesne severity index
SF-36 Quality of Life Questionnnaire
Poor Cartilage Index – MRI
VAS
WOMAC
Lequesne severity index
Poor Cartilage Index – MRI
VAS
Functional rating index
RoM
MRI evaluation of cartilage

Hip (n = Ankle (n = 2)

ed/ ADSC

IKDC – subjective Tegner Lysholm Knee VAS for pain WOMAC
HAQ, pain subscale SF-36 Lequesne functional index MRI T2 mapping WOMAC
KOOS
VAS for pain

BMSC

(2013)

ACCEPTED MANUSCRIPT

Varma (2010)

India IV

50 (X/X)

Knee BMAC/ BMSC

n/a

6 mo

Wakitani (2011)

Japan IV

26 (X/X)

Culture- Knee expanded

Collagen gel sheet

Adverse events: tumor development and infection

Mean: 75 mo

Wei (2011)

USA IV

23 (17/6)

Knee BMAC/ BMSC

PRP

WOMAC
VAS for pain
Patient Global Assessment 50 foot walk pain Physician Global Assessment VAS for pain
JKOM
WOMAC

12 mo

Yokota (2017)

Japan IV

13 (4/22)**

Knee SVF/ ADSC

n/a

6 mo

Centeno (2008)

USA V

1(0/1)

Culture- Knee expanded

Autologous whole- marrow, platelet lysate, dexamethasone Hyoluronate sodium, autologous whole- marrow, platelet lysate, dexamethasone Autologous marrow- derived nucleated cells, platelet lysate, dexamethasone

Modified VAS Functional Rating Index ROM
MRI quantitative volume analysis

3 mo

Centeno (2008)

USA V

1(1/0)

Culture- Knee expanded

Modified VAS Functional Rating Index ROM
MRI quantitative volume analysis

3 mo

Centeno (2008)

USA V

1 (1/0)

Culture- Knee expanded

Modified VAS Functional Rating Index ROM
MRI quantitative volume analysis WOMAC
VAS for pain
Walking distance
Time to gelling
Patellar crepitus
RoM
MRI cartilage assessment VAS for pain Functional rating index RoM
MRI assessment of cartilage

6 mo

Mehrabani (2016)

Iran V

1 (0/1)

Culture- Knee expanded

n/a

12mo

Pak (2017)

100

Korea V

1 (0/1)

Hip SVF/ ADSC

ECM, Hyaluronic acid, PRP

20 wks

ACCEPTED MANUSCRIPT

Lysholm score
MRI cartilage assessment VAS
OAOS

BMSC

stem cell; MSC = mesenchymal stem cell; OA = osteoarthritis; PBSC = peripheral blood stem cell; BMAC = bone marrow aspirate stem cell concentrate

ADSC = adipose-derived stem cell; BMSC = bone-marrow
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

ACCEPTED MANUSCRIPT

First Author (Date of Publication)

Participant Selection

Risk due to… Deviations

Missing Outcomes Data Measurement

Selection of
Reported Overall

Garay-Mendoza

Low Low Low

Low Low

(2017)

29 Low

Gupta (2016) Low

Low Low Low

Low Low

Lamo-Espinosa

Low Low Low

Low Low

(2016)

90 Low

96
Turajane (2017) Low

Low Low Low Low Low Low Low Moderate Moderate Low Low Moderate Low Moderate Moderate

Low Low Low Low Low Moderate Low Moderate Low Moderate

97
Vega (2015) Low

Centeno (2014) Jo (2014)

Nguyen (2016) Pers (2016)

91 13

Moderate Moderate Moderate

Low Low Low

Low Moderate Moderate

Jo (2017)
Koh (2014) Low

Some
Low Low concerns

Some concerns Moderate Moderate Low Moderate

Low

30 100

Low Low

Low Moderate

Low Low Moderate Moderate Moderate Moderate

95
Shapiro (2017) Low

Low Low

Some concerns

Low

Some concerns

Wakitani (2002)

98 Some concerns

Some Some concerns concerns

Some concerns Some concerns

High High

Wong (2013)

Some concerns

Low
Low Low

Some concerns

Randomized Process

Confounding

Intervention Classification

from Intended Intervention

ACCEPTED MANUSCRIPT

Table 3. Risk of Bias assessment using Cochrane’s RoB 2.0 Scale for level I evidence studies and ROBINS-I scale for level II evidence studies. NI = no information

Result

Table 4. Intervention details of the included level I and II evidence studies

ACCEPTED MANUSCRIPT

First Author (Date of Publication)

MSC Type & Extraction Site

BMAC/BMSC: iliac crest

Allogeneic CE BMSC: from 3 healthy volunteers

CE BMSC: iliac crest

PBSC

Allogeneic culture- expanded BMSC: iliac crest

CE BMSC: iliac crest

CE ADSC: SQ abdominal fat

SVF/ADSC: SQ buttocks

SVF/ADSC: SQ abdominal fat

CE ADSC: SQ abdominal fat

BMAC/BMSC: iliac crest

CE BMSC: iliac crest

Biologic Adjuvant

Outpatient
SQ G-CSF x 3 days

PLASMALYTE-A Pre: Hydrocortisone and pheniramine maleate
Post: Hyaluronic acid

Hyaluronic acid

Hyaluronic acid, GFA (PRP, hG-CSF)

n/a

Platelet lysate

Injection Procedure

Intra-articular injection of 10mL concentrate without radiographic guidance

Pre-medication of hydrocortisone and pheniramine maleate. Intra-articular injection without radiographic guidance followed by HA

Intra-articular injection without radiographic guidance

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

Intra-articular injection without radiographic guidance

Intra-articular injection with radiographic and fluoroscopic guidance

Number of Injected MSCs

10 ml concentrate

7 TNC: 302.2 x 10

Mononuclear:

7 67.33 x 10

+
CD34 : 20.56 x

6 10

4 dose levels: 25,

6 50, 75, 150 x 10

Low-dose: 10 x

6 10

High-dose: 100 x

6 10

Follow-up

1 wk, 1, 6 mo

12 mo

3, 6, 12 mo

1, 6, 12 mo

8 days, 3, 6, 12 mo

3, 6, & 12 mo

Number of Injections

Garay-Mendoza

(2017)

Gupta (2016)

Turajane

(2017)

Centeno

(2014)

Jo (2017)

Nguyen

Lamo-Espinosa

(2016)

3 ml PBSC Range TNC: 1.095-1.276 x 10

6 40 x 10

6 5.76 x 10

Low-dose: 10 x

6 10

Vega (2015)

Jo (2014)

Koh (2014)

(2016)

Shapiro

(2017)

Pers (2016)

100

Wong (2013)99

n/a

PRP

n/a

Platelet-poor bone marrow plasma

Collagen gel sheet

Hyaluronic acid

saline

Intra-articular injection with 3mL saline

Intra-articular arthroscopic-guided injection followed by open-wedge HTO

Intra-articular injection with 5ml SVF + PRP

Intra-articular injection with ultrasound guidance

Ultrasoundguidedintra-articular injection of 5 ml BMAC with 10 ml platelet-poor bone marrow plasma

HTO followed by collagen cell sheet with cells implanted
HTO and microfracture followed 3 weeks later with intra-articular injection with 2ml HA

12, 24 mo

Mean 24.2± 4.7 mo

1,6,12,18mo

6 mo

1 wk, 3 mo, 6 mo

Mean: 16 months

every 6 weeks for 6 mo, 1, 2 yrs

1 MSC 3 HA

Intra-articular injection with 3mL
n/a 66mo1

Mid-dose: 50 x 10 High-dose: 100 x

Low-dose: 10 x

6 10

Mid-dose: 50 x

6 10

High-dose: 100 x

6 10

120 ml of SVF

Estimated

8.5% of 4.83 x

7
10 SVFcells

6 (4.11 x 10 )

7
10 SVFcells/ml

6 Low-dose: 2 x 10

Mid-dose: 10 x

6 10

High-dose: 50 x

Median of 3.4 x

4
10 MSCsand

6 4.62 x 10

hematopoietic

stem cells

7 1.3 x 10

6 1.46 ± 0.29 x 10

6 10

Wakitani

(2002)

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

ACCEPTED MANUSCRIPT

Table 5. Outcome assessments of the included level I and II evidence studies First Author

MSC-groups Significant Improvement from Baseline

Comparison group Scores: Baseline vs. Final F/U

Significant improvement with comparison

(Date of Publication)

Comparison Groups

Outcomes Measures

MSC group Scores: Baseline vs. Final F/U (x ± SD)

Garay-Mendoza

Acetaminophen 500 mg every 8 hours for 6 months

VAS WOMAC* Safety

5.27 ± 2.196 vs. 0.92 ± 1.29
62.61 ± 18.55 vs. 91.73 ±9.45 Swelling, pain, stiffness
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

4.32 ± 2.35 vs. 4.64 ± 2.43 6.93 ± 17.89 vs. 72.96 ± 15.04 Swelling, pain, stiffness Placebo cohort 1:

Yes, p<0.0001 Yes, p<0.0001

(2017)

Gupta (2016)

WOMAC

No, p > 0.05 due to small sample size

1239.6 ± 472.2 vs. 233.8 ± 641.9

Lamo-Espinosa

Radiographic (WORMS, X-Ray)

MRI (WORMS): decreased joint damage X-ray: no change in joint space width Flexion measurement:

N/A

MRI (WORMS): no change in joint damage
X-ray: reduction in joint space width

N/A

(2016)

Placebo: HA alone

Turajane

With cohort 1:

(2017)

Cohort 1: 218.5 vs. 52 Cohort 2: 212.2 vs. 75

Yes, p < 0.0001 Yes, p < 0.0001

Yes, p < 0.001

Vega (2015)

SE WOMAC

Dose-escalation cohorts

Low dose: 1315.8 ± 444.8 vs. 717.8 ± Low dose: 1498.4 ± 407.4 vs. 359.9 ± High dose: 1470.6 ± 471.0 vs N/A High dose: 1388.1 ± 508.8 vs N/A

503.8 786.4

Placebo cohort 1:

No, p=0.28 No, p=0.9

Placebo: injection of PLASMA-LYTE A

Placebo cohort 2:

Dose escalation cohorts

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)

Yes, p < 0.009 N/A

Cohort 1: PBSCs, HA, PRP, hG-CSF, and microdrilling treatment Cohort 2: like cohort 1 but without hG-CSF

Safety
Need for surgical intervention at 12 months

High dose: 177 (174,180) vs. 180 (180,180) No adverse events besides mild pain
Cohort 1:0 patients need joint replacement Cohort 2:0 patients need joint replacement

N/A

No adverse events besides mild pain 3 need joint replacement

N/A
Yes, p < 0.033

Placebo: HA alone

Yes, p < 0.001

Placebo: HA alone

SE VAS

54 ± 7 vs. 33 ± 6 41 ± 3 vs. 28 ± 5 39 ± 4 vs. 30 ± 3

N/A N/A N/A

64 ± 7 vs. 51 ± 8 45 ± 3 vs. 41 ± 6 45 ± 4 vs. 42 ± 5

Yes, p< 0.005 Yes, p< 0.005 Yes, p< 0.005

VAS

No, p > 0.05 due to small sample size

61.0 ± 23.8 vs. 39.7 ± 28.3

No, p=0.24 No, p=0.11

ICOAP

No, p > 0.05 due to small sample size

49.3 ± 18.7 vs. 7.5 ± 27.1

Radiographic (WORMS)

N/A

76.5 ± 23.5 vs. 74.9 ± 22.5

Safety

Pain and swelling
One serious event: synovial effusion

N/A

Pain and swelling

N/A

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)

Yes, p = 0.005

Knee Flexion and Extension Measurements

Low dose: 116 (110,116) vs. 119 (116,122) High dose: 110 (110,117) vs. 118(116, 122)

Yes, p < 0.05 Yes, p < 0.05

Flexion:
118 (114,120) vs. 118 (115,118)

N/A

WOMAC

215.3 vs. 126.8

With cohort 2:

SE Lequesne score

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

Placebo cohort 1:

No, p=0.38 No, p=0.54

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

Placebo cohort 1:

No, p=0.5310 No, p=0.0609

ACCEPTED MANUSCRIPT

Extension measurement:
Low dose: 176 (173,180) vs. 180 (176, 180)

Extension:

Yes, p < 0.05 Yes, p < 0.05 N/A

180 (176, 180) vs. 179 (175, 180)

Placebo cohort 2:

65.3 ± 12.2 vs. 43.4 ± N/A

Placebo cohort 2:

54.8 ± 17.8 vs. N/A

1392.0 ± 324.7 vs. N/A

Placebo cohort 2:

70.8 ± 14.7 vs. 72.3 ± 15.3

With low dose cohort:

With high dose cohort:

ACCEPTED MANUSCRIPT

Centeno

Untreated procedure candidates
(No placebo)

60% improvement

19 % improvement

Yes, p = 0.03

(2014)

Jo (2014)

Dose-escalation cohorts
(No placebo)

Jo (2017)

Dose-escalation cohorts
(No placebo)

KSS Knee 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

Yes, p = 0.031 No, p = 0.241 Yes, p =< 0.001

N/A

SF-12 PCS

40 ± 9 vs. 45 ± 11

No, p > 0.05

35±8vs.40±8

No, p > 0.05

SF-12 MCS

54 ± 10 vs. 51 ± 12

No, p > 0.05

49±9vs.47±11

No, p > 0.05

MRI (PCI)
Safety
-100% to +100% pain relief scale
VAS

Decreased significantly by 1 year Inflammation during first 7 days

Yes, p < 0.05 N/A

Does not drop significantly by 1 year Inflammation during first 7 days

No, p > 0.05 N/A

SE WOMAC

63% improvement (5.2 vs. 2.0)
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 treatment-related adverse events 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 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

No, p = 0.339 No, p= 0.391 Yes, p = 0.003 N/A

N/A N/A N/A

Safety
VAS
KSS Knee score

No, p = 0.069 No, p = 0.486 Yes, p = 0.000 Yes, p = 0.025 No, p = 0.324 Yes, p = 0.000

KSS Function score

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 = 0.020 No, p = 0.333 No, p = 0.120

N/A

Radiographic: depth of cartilage defect,

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

Yes, p < .05

N/A

Radiographic: articular cartilage volume)

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 < 0.05

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

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

KSS Function score

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 = 0.015
No, p = 0.439
Yes, p = 0.026
But, plateaus at 1 year F/U

N/A

KOOS pain 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

No, p = 0.148 No, p= 0.220 Yes, p < 0.001

KOOS symptom score

Low dose: 61.9 ± 7.2 vs. 72.6 ± 5.2

Yes, p = 0.035

ACCEPTED MANUSCRIPT

N/A

ACCEPTED MANUSCRIPT

Koh (2014)

PRP alone

Nguyen (2016)

30 Arthroscopic microfracture alone

2.67 6 0.62 vs. 1.40 6 0.51

Pers (2016)100

KOOS symptom scale Lysholm score

82.8 7.2 vs. N/A
55.7 ± 11.5 vs. 84.7 ± 16.2

N/A N/A

75.4 ± 8.5
56.7 ± 12.2 vs. 80.6 ± 13.5

Yes, p = 0.006 No, p = 0.357

Dose-escalation cohorts
(No placebo)

WOMAC

N/A

KOOS activities of daily living score

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

Yes, p = 0.001 No, p = 0.237 Yes, p < 0.001

N/A

Radiographic (MRI)

N/A

VAS
KOOS pain scale

44.3 ± 5.7 vs. 10.2 ± 5.7 81.2 ± 6.9 vs N/A

N/A

45.4 ± 7.1 vs. 16.2 ± 4.6 74.0 ±5.7

Yes, p < 0.001 Yes, p < 0.001

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

WOMAC

42.87 ± 16.29 vs. 17.33 ± 14.91 53.47 ± 14.56 vs. 84.73 ± 19.54

N/A

47.37 ± 17.13 vs. 37.08 ± 21.45 64.13 ± 10.19 vs. 65.17 ± 14.74

Yes, p < 0.05

Lysolm score

N/A

Yes, p < 0.05

VAS for pain

1.60 ± 0.83 vs. 3.47 ± 0.74

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

Safety

Only one severe adverse event
(UA in a patient with multiple risk factors)

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 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 Lowdose:34±15vs.65.8±9.1 Mid-dose: 42 ± 9 vs. 59.2 ± 6.5

Yes, p < 0.05 No, p = 0.09 No, p = 0.54 Yes, p < 0.001 No, p = 0.054 No, p = 0.38 Yes, p < 0.01 Yes, p < 0.05 No,p=0.32 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

KOOS

N/A

SF-36 PCS

High dose: 45.2 ± 13.6 vs. 65.2 ± 13.1 Low dose: 30.9 ± 8.2 vs. 39.1 ± 4.6 Mid-dose: 29.9 ± 6.2 vs. 35.3 ± 4.0

N/A

SF-36 MCS

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

N/A

Mid-dose: 39.3 ± 16.4 vs. 76.9 ± 10.5 High dose: 48.5 ± 5.3 vs. 72.9 ± 5.2

No, p = 0.214 Yes, p = 0.003

N/A

ACCEPTED MANUSCRIPT

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**

ACCEPTED MANUSCRIPT

Shapiro (2017)

Wakitani (2002)98

Cell-free collagen gel- sheet implantation

Arthroscopic/histologic cartilage evaluation

7.5± 2.2 vs. 10.0 ± 6.1 8.0 ± 0.9 vs. 11.3 ± 2.3

Wong (2013)

HTO + HA alone

Saline into each patient’s contralateral knee. Patient blinded to knee with treatment versus placebo.

32 vs. 9

VAS for pain ICOAP

3.1 vs. 1.5 32 vs. 16

Yes, p = 0.001 Yes, p = 0.0005

2.9 vs. 0.8

No, p = 0.44 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

HSS Knee Rating Scale

65.0 ± 6.7 vs. 81.3 ± 8.6 9.8 ± 2.0 vs. 15.4 ± 1.4

Yes, p = 0.0029

66.3 ± 10.5 vs. 79.2 ± 8.7

No, p > 0.05 Yes, p < 0.05

Lysholm score

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

33.9 ± 11.4 vs. N/A Improvement of 7.65 62.32 ± 17.56

Yes, p = 0.001

36.0 ± 13.7 vs. N/A 43.21 ± 13.55

Yes, p = 0.001 Yes, p < 0.001

IKDC
Radiographic (MOCART)

ACCEPTED MANUSCRIPT

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

* 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 2years

study reported standard error instead of standard deviation for this outcome measure

ACCEPTED MANUSCRIPT

Figure Legends:

Figure 1. Osteoarthritis and Stem Cell Therapy PRISMA Flow Diagram

ACCEPTED MANUSCRIPT

Figure 1. PRISMA Flow Diagram

ACCEPTED MANUSCRIPT

Records identified through database searching
(n = 3416)

Records after duplicates removed (n = 3172)

Additional records identified through other sources
(n = 9)

Records screened (n = 3172)

Full-text articles excluded, with reasons
(n = 350)

• Not human clinical trial

• Not in English

• In vitro study

• MSCs not used for direct
treatment of OA

• Review article

• Letter to the editor

• Conference
submission/Abstract only

• Isolated, focal chondral
defects not associated with OA

Full-text articles assessed for eligibility
(n = 381)

Records excluded (n = 2783)

Studies included in qualitative synthesis (n = 61)

Studies included in quantitative synthesis (meta-analysis)
(n = 14)

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta- Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097

For more information, visit http://www.prisma-statement.org.

Included Eligibility Screening Identification

ACCEPTED MANUSCRIPT

Appendix A. Search strategy and initial results

PubMed/MEDLINE search:
No filters or limits used (language, date, etc):
((“stem cells”[MeSH Terms] OR “stem cells”[All Fields] OR “stem cell”[All Fields])) AND ((((“osteoarthritis”[MeSH Terms] OR “osteoarthritis”[All Fields])) OR osteo-arthrit*) OR osteoarthrit*)

EMBASE search: Search Strategy:

Searches

Results

exp osteoarthritis/

111043

osteoarthrit*.ti,ab.

76202

osteo-arthrit*.ti,ab.

481

stem cell?.ti,ab.

317076

exp stem cell/

309122

1 or 2 or 3

125709

4 or 5

419786

6 and 7

2662

EBM Reviews – Cochrane Central Register of Controlled Trials:

Search Strategy:

Searches

Results

exp Osteoarthritis/

4026

osteoarthrit*.mp.

8725

osteo-arthrit*.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword]

1 or 2 or 3

8744

exp Stem Cells/

669

stem cell?.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword]

7293

5 or 6

7342

4 and 7

CINAHLPlus via Ebsco Search Strategy:

ACCEPTED MANUSCRIPT

Searched using full text expanders. # Query
S8 S4 AND S7
S7 S5ORS6

S6 TX stem cell*
S5 (MH “Stem Cells+”) S4 S1ORS2ORS3
S3 osteo-arthrit*
S2 TX osteoarthrit*
S1 (MH “Osteoarthritis+”)

ACCEPTED MANUSCRIPT

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