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Osteoarthritis and stem cell therapy in humans: a systematic review

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
      • Arden N.
      • Nevitt M.C.
      Osteoarthritis: epidemiology.
      • Neogi T.
      • Zhang Y.
      Epidemiology of osteoarthritis.
      . While worldwide prevalences of knee and hip OA are 3.8% and 0.85% respectively, this burden is likely underestimated.
      • Cross M.
      • Smith E.
      • Hoy D.
      • Nolte S.
      • Ackerman I.
      • Fransen M.
      • et al.
      The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study.
      OA is the common end-point of many different pathologies. As such, its etiology is varied, involving both intrinsic joint and extrinsic environmental factors. Age, gender, menopause, genetics, nutrition and bone density often lead to increased susceptibility to OA. These systemic factors, in addition to mechanical factors such as weight/body mass index, injury, surgery, and deformity help determine the location and severity of an individual's OA
      • Arden N.
      • Nevitt M.C.
      Osteoarthritis: epidemiology.
      . Additionally, elevated inflammatory cytokines such as IL-1β and TNFα have recently been implicated in OA's pathogenesis.
      • Sokolove J.
      • Lepus C.M.
      Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations.
      Existing treatments for OA are largely unsatisfactory. Pharmacologic management includes acetaminophen, aspirin and oral non-steroidal anti-inflammatory drugs (NSAIDs)
      • 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.
      • Zhang W.
      • Nuki G.
      • Moskowitz R.W.
      • Abramson S.
      • Altman R.D.
      • Arden N.K.
      • et al.
      OARSI recommendations for the management of hip and knee osteoarthritis: part III: changes in evidence following systematic cumulative update of research published through January 2009.
      . Other options include capsaicin, duloxetine, topical NSAIDs and intra-articular corticosteroid injections
      • Conaghan P.G.
      • Dickson J.
      • Grant R.L.
      Care and management of osteoarthritis in adults: summary of NICE guidance.
      • McAlindon T.E.
      • Bannuru R.R.
      • Sullivan M.C.
      • Arden N.K.
      • Berenbaum F.
      • Bierma-Zeinstra S.M.
      • et al.
      OARSI guidelines for the non-surgical management of knee osteoarthritis.
      • 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.
      . These drugs are recommended secondarily to patient education, strengthening exercises, and weight loss. Physical and occupational therapy have also demonstrated beneficial effects
      • 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.
      • Zhang W.
      • Nuki G.
      • Moskowitz R.W.
      • Abramson S.
      • Altman R.D.
      • Arden N.K.
      • et al.
      OARSI recommendations for the management of hip and knee osteoarthritis: part III: changes in evidence following systematic cumulative update of research published through January 2009.
      .
      These conservative treatments may be sufficient for early management, but their role in modifying underlying structural abnormalities is limited. The OA Research Society International suggests patients consider surgical interventions if daily pain persists for months and conservative management has failed
      • Zhang W.
      • Nuki G.
      • Moskowitz R.W.
      • Abramson S.
      • Altman R.D.
      • Arden N.K.
      • et al.
      OARSI recommendations for the management of hip and knee osteoarthritis: part III: changes in evidence following systematic cumulative update of research published through January 2009.
      . Total joint replacements have thus become important in the management of severe OA. In elderly populations, the prevalence of joint replacements due to OA is 13.6%
      • Jonsson H.
      • Olafsdottir S.
      • Sigurdardottir S.
      • Aspelund T.
      • Eiriksdottir G.
      • Sigurdsson S.
      • et al.
      Incidence and prevalence of total joint replacements due to osteoarthritis in the elderly: risk factors and factors associated with late life prevalence in the AGES-Reykjavik Study.
      . However, ongoing research aims to develop less invasive procedures for management.
      Less invasive procedures such as intra-articular injections of hyaluronic acid (HA), platelet rich plasma (PRP), hypertonic dextrose prolotherapy and anabolic cartilaginous agents are being studied as potential therapies
      • Patel S.
      • Dhillon M.S.
      • Aggarwal S.
      • Marwaha N.
      • Jain A.
      Treatment with platelet-rich plasma is more effective than placebo for knee osteoarthritis: a prospective, double-blind, randomized trial.
      • Rabago D.
      • Patterson J.J.
      • Mundt M.
      • Kijowski R.
      • Grettie J.
      • Segal N.A.
      • et al.
      Dextrose prolotherapy for knee osteoarthritis: a randomized controlled trial.
      • Wang C.T.
      • Lin J.
      • Chang C.J.
      • Lin Y.T.
      • Hou S.M.
      Therapeutic effects of hyaluronic acid on osteoarthritis of the knee. A meta-analysis of randomized controlled trials.
      . Intra-articular injection of mesenchymal stem cells (MSCs) is an increasingly common adjuvant therapy that has shown promising results. A 2014 proof-of-concept trial demonstrated that intra-articular injection of MSCs into OA knees improved function and pain without adverse events
      • 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.
      . Regeneration of hyaline-like articular cartilage was noted
      • 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.
      . Critics, however, are skeptical of the quality of evidence and cost of cell-based therapies
      • Diekman B.O.
      • Guilak F.
      Stem cell-based therapies for osteoarthritis: challenges and opportunities.
      .
      To date, few MSC-related adverse events have been noted
      • 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.
      . In a systematic review of the safety of intra-articular therapy, 844 procedures (mean follow-up 21 months) were analyzed to find only four serious adverse events: one infection post-bone marrow aspiration that resolved with antibiotics, one pulmonary embolus two weeks after aspiration, and two adverse events reported as unrelated to the therapy. Other sequelae included pain, swelling and dehydration after aspiration
      • Peeters C.M.
      • Leijs M.J.
      • Reijman M.
      • van Osch G.J.
      • Bos P.K.
      Safety of intra-articular cell-therapy with culture-expanded stem cells in humans: a systematic literature review.
      . A more recent assessment of adverse events of autologous stem cell therapies found they primarily included post-procedural pain or pain due to progressive degenerative joint disease in under 4% of the population.
      • Centeno C.J.
      • Al-Sayegh H.
      • Freeman M.D.
      • Smith J.
      • Murrell W.D.
      • Bubnov R.
      A multi-center analysis of adverse events among two thousand, three hundred and seventy two adult patients undergoing adult autologous stem cell therapy for orthopaedic conditions.
      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
      • Dominici M.
      • Le Blanc K.
      • Mueller I.
      • Slaper-Cortenbach I.
      • Marini F.
      • Krause D.
      • et al.
      Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.
      • Rodriguez-Fontan F.
      • Piuzzi N.S.
      • Chahla J.
      • Payne K.A.
      • LaPrade R.F.
      • Muschler G.F.
      • et al.
      Stem and progenitor cells for cartilage repair: source, safety, evidence, and efficacy.
      . However, the term MSC is not always used in the literature with this definition in mind. Evidence supporting the immunomodulatory role of MSCs suggests the term “stem cell” is a misnomer and the name be changed to medicinal signaling cells
      • Caplan A.I.
      Mesenchymal stem cells: time to change the name!.
      , though this change has yet to be reflected in the literature. The immunomodulatory properties of MSCs, however, have been postulated to have the capacity to play a role in manipulation of the disease process. These properties include anti-inflammatory, anti-apoptotive, anti-fibrotic, angiogenic, mitogenic and wound-healing paracrine activity.
      • Caplan A.I.
      Why are MSCs therapeutic? New data: new insight.
      • Freitag J.
      • Bates D.
      • Boyd R.
      • Shah K.
      • Barnard A.
      • Huguenin L.
      • et al.
      Mesenchymal stem cell therapy in the treatment of osteoarthritis: reparative pathways, safety and efficacy - a review.
      MSCs can be harvested from several sites including bone marrow (BMSCs), adipose tissue (ADSCs), synovium (SDSCs) or peripheral blood (PBSCs)
      • Rodriguez-Fontan F.
      • Piuzzi N.S.
      • Chahla J.
      • Payne K.A.
      • LaPrade R.F.
      • Muschler G.F.
      • et al.
      Stem and progenitor cells for cartilage repair: source, safety, evidence, and efficacy.
      . BMSCs and ADSCs have received considerable attention due to their ease of extraction
      • Filardo G.
      • Madry H.
      • Jelic M.
      • Roffi A.
      • Cucchiarini M.
      • Kon E.
      Mesenchymal stem cells for the treatment of cartilage lesions: from preclinical findings to clinical application in orthopaedics.
      . Once removed, typically from the iliac crest, BMSCs can be expanded in culture and induced to various stages of differentiation
      • Filardo G.
      • Madry H.
      • Jelic M.
      • Roffi A.
      • Cucchiarini M.
      • Kon E.
      Mesenchymal stem cells for the treatment of cartilage lesions: from preclinical findings to clinical application in orthopaedics.
      • 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.
      . Adipose tissue is abundant, making ADSC procurement easy and minimally invasive
      • De Ugarte D.A.
      • Morizono K.
      • Elbarbary A.
      • Alfonso Z.
      • Zuk P.A.
      • Zhu M.
      • et al.
      Comparison of multi-lineage cells from human adipose tissue and bone marrow.
      . ADSCs can differentiate into fat, bone or cartilage
      • Zuk P.A.
      • Zhu M.
      • Ashjian P.
      • De Ugarte D.A.
      • Huang J.I.
      • Mizuno H.
      • et al.
      Human adipose tissue is a source of multipotent stem cells.
      . These cells are harvested from infra-patellar fat pads or subcutaneous sites such as the buttocks
      • Kim Y.S.
      • Choi Y.J.
      • Koh Y.G.
      Mesenchymal stem cell implantation in knee osteoarthritis: an assessment of the factors influencing clinical outcomes.
      . There is debate regarding the differences between BMSCs and ADSCs in terms of cell yield, growth kinetics, and differentiation capacity
      • De Ugarte D.A.
      • Morizono K.
      • Elbarbary A.
      • Alfonso Z.
      • Zuk P.A.
      • Zhu M.
      • et al.
      Comparison of multi-lineage cells from human adipose tissue and bone marrow.
      • Al-Nbaheen M.
      • Vishnubalaji R.
      • Ali D.
      • Bouslimi A.
      • Al-Jassir F.
      • Megges M.
      • et al.
      Human stromal (mesenchymal) stem cells from bone marrow, adipose tissue and skin exhibit differences in molecular phenotype and differentiation potential.
      . However, both animal and human models have shown positive results for OA treatment with these MSC types
      • Al Faqeh H.
      • Nor Hamdan B.M.
      • Chen H.C.
      • Aminuddin B.S.
      • Ruszymah B.H.
      The potential of intra-articular injection of chondrogenic-induced bone marrow stem cells to retard the progression of osteoarthritis in a sheep model.
      • 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.
      • 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.
      . SDSCs, often harvested from the knee, are recognized for their differentiation potential and high cell yield
      • 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.
      . PBSCs are collected via minimally invasive apheresis but are used less frequently
      • 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.
      . When freshly collected, PBSCs do not display MSC markers unless in hypoxic conditions
      • Hopper N.
      • Wardale J.
      • Brooks R.
      • Power J.
      • Rushton N.
      • Henson F.
      Peripheral blood mononuclear cells enhance cartilage repair in in vivo osteochondral defect model.
      or after subcutaneous administration of human granulocyte colony stimulating factor prior to blood draw
      • Saw K.Y.
      • Anz A.
      • Merican S.
      • Tay Y.G.
      • Ragavanaidu K.
      • Jee C.S.
      • et al.
      Articular cartilage regeneration with autologous peripheral blood progenitor cells and hyaluronic acid after arthroscopic subchondral drilling: a report of 5 cases with histology.
      .
      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
      • Zuk P.A.
      • Zhu M.
      • Ashjian P.
      • De Ugarte D.A.
      • Huang J.I.
      • Mizuno H.
      • et al.
      Human adipose tissue is a source of multipotent stem cells.
      • Baer P.C.
      • Geiger H.
      Adipose-derived mesenchymal stromal/stem cells: tissue localization, characterization, and heterogeneity.
      • 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.
      . 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
      • Cotter E.J.
      • Wang K.C.
      • Yanke A.B.
      • Chubinskaya S.
      Bone marrow aspirate concentrate for cartilage defects of the knee: from bench to bedside evidence.
      . 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
      • Baer P.C.
      • Geiger H.
      Adipose-derived mesenchymal stromal/stem cells: tissue localization, characterization, and heterogeneity.
      • 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
      • Tremolada C.
      • Colombo V.
      • Ventura C.
      Adipose tissue and mesenchymal stem cells: state of the art and lipogems(R) technology development.
      .
      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)
      • 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
      • 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
      • 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)
      • Higgins J.
      • Sterne J.A.C.
      • Savović J.
      • Page M.J.
      • Hróbjartsson A.
      • Boutron I.
      • et al.
      A revised tool for assessing risk of bias in randomized trials.
      and Risk of Bias In Non-randomised Studies – of Intervention (ROBINS-I) tool
      • Sterne Jonathan AC.
      • Hernán Miguel A.
      • Reeves Barnaby C.
      • Savović Jelena
      • Berkman Nancy D.
      • Viswanathan Meera
      • et al.
      ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions.
      .

      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.

      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
      • 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.
      • 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.
      • 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.
      • 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.
      • 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.
      • 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.
      • Centeno C.
      • Pitts J.
      • Al-Sayegh H.
      • Freeman M.
      Efficacy of autologous bone marrow concentrate for knee osteoarthritis with and without adipose graft.
      • 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.
      • 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.
      • 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.
      • 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.
      • 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.
      • 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.
      • Davatchi F.
      • Abdollahi B.S.
      • Mohyeddin M.
      • Shahram F.
      • Nikbin B.
      Mesenchymal stem cell therapy for knee osteoarthritis. Preliminary report of four patients.
      • Davatchi F.
      • Sadeghi Abdollahi B.
      • Mohyeddin M.
      • Nikbin B.
      Mesenchymal stem cell therapy for knee osteoarthritis: 5 years follow-up of three patients.
      • 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.
      • Fodor P.B.
      • Paulseth S.G.
      Adipose derived stromal cell (ADSC) injections for pain management of osteoarthritis in the human knee joint.
      • 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.
      • 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.
      • 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.
      • 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?.
      • 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.
      • 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.
      • Kim Y.S.
      • Lee M.
      • Koh Y.G.
      Additional mesenchymal stem cell injection improves the outcomes of marrow stimulation combined with supramalleolar osteotomy in varus ankle osteoarthritis: short-term clinical results with second-look arthroscopic evaluation.
      • 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.
      • 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.
      • Koh Y.G.
      • Choi Y.J.
      Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis.
      • 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.
      • Mardones R.
      • Jofre C.M.
      • Tobar L.
      • Minguell J.J.
      Mesenchymal stem cell therapy in the treatment of hip osteoarthritis.
      • 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.
      • 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.
      • 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.
      • 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.
      • 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.
      • 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.
      • 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.
      • Pak J.
      • Lee J.H.
      • Park K.S.
      • Lee S.H.
      Efficacy of autologous adipose tissue-derived stem cells with extracellular matrix and hyaluronic acid on human hip osteoarthritis.
      • Park Y.B.
      • Ha C.W.
      • Lee C.H.
      • Yoon Y.C.
      • Park Y.G.
      Cartilage regeneration in osteoarthritic patients by a composite of allogeneic umbilical cord blood-derived mesenchymal stem cells and hyaluronate hydrogel: results from a clinical trial for safety and proof-of-concept with 7 years of extended follow-up.
      • 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.
      • Russo A.
      • Condello V.
      • Madonna V.
      • Guerriero M.
      • Zorzi C.
      Autologous and micro-fragmented adipose tissue for the treatment of diffuse degenerative knee osteoarthritis.
      • 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.
      • Varma H.S.
      • Dadarya B.
      • Vidyarthi A.
      The new avenues in the management of osteo-arthritis of knee - stem cells.
      • 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.
      • 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.
      • 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.
      • 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.
      • Oliver K.
      • Bayes M.
      • Crane D.
      • Pathikonda C.
      Clinical outcome of bone marrow concentrate in knee osteoarthritis.
      • 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).
      • 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.
      • 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.
      • 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.
      • 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.
      • 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.
      • 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.
      • 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.
      • 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.
      • 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.
      • 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.
      • Mamidi M.K.
      • Das A.K.
      • Zakaria Z.
      • Bhonde R.
      Mesenchymal stromal cells for cartilage repair in osteoarthritis.

      FDA US. 21 CFR 1271.3 - How Does FDA Define Important Terms in This Part? Code of Federal Regulations - Title 21: Food and Drugs. In: Services DoHaH, editor. 2016.

      • Centeno C.J.
      • Faulkner S.
      The use of mesenchymal stem cells in orthopedics: review of the literature, current research, and regulatory landscape.
      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 siteMSC 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.
      Knee51ADSC 29CE3I5
      Ankle3SVF24II9
      Micro2
      Hand2BMSC 30CE18III7
      Shoulder1BMAC10IV35
      Hip2Allog2
      Multiple Knee/Hip/Ankle2PBSC3V5
      Allog hUCB-MSCs1
      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
      • Kim Y.S.
      • Choi Y.J.
      • Koh Y.G.
      Mesenchymal stem cell implantation in knee osteoarthritis: an assessment of the factors influencing clinical outcomes.
      • 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)
      • 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)
      • 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.
      • Varma H.S.
      • Dadarya B.
      • Vidyarthi A.
      The new avenues in the management of osteo-arthritis of knee - stem cells.
      • 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.
      • 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.
      .
      Table IIStudy characteristics of the included clinical studies grouped by level of evidence
      First Author (Date of publication)Country of originLevel of evidence
      • Fodor P.B.
      • Paulseth S.G.
      Adipose derived stromal cell (ADSC) injections for pain management of osteoarthritis in the human knee joint.
      N
      N = number of patients in the treatment group.
      (Male/Female)
      OA siteMSC Source/TypeBiologic adjuvantOutcome measuresFollow-up length of time
      Garay-Mendoza (2017)
      • 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.
      MexicoI30 (7/23)KneeBMAC/BMSCOutpatient

      SQ G-CSF x 3 days
      VAS

      WOMAC
      6 mo
      Gupta (2016)
      • 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.
      IndiaI40 (12/28)KneeAllogeneic culture-expanded BMSCPLASMALYTE-A

      Pre: Hydrocortisone and pheniramine maleate

      Post: Hyaluronic acid
      VAS for pain

      ICOAP

      WOMAC

      WORMS – knee
      12 mo
      Lamo-Espinosa (2016)
      • 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).
      SpainI20 (12/8)KneeCulture-expanded BMSCHyaluronic acidVAS

      WOMAC

      RoM

      X-Ray knee joint space width

      WORMS
      12 mo
      Turajane (2017)
      • 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.
      ThailandI40 (13/27)KneePBSCHyaluronic acid, GFA (PRP, hG-CSF)Need for surgical intervention at 12mo

      WOMAC
      12 mo
      Vega (2015)
      • 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.
      SpainI15 (6/9)KneeAllogeneic

      culture-expanded BMSC
      n/aVAS

      WOMAC

      Lequesne functional index

      SF-12 life quality questionnaire

      MRI T2 mapping, PCI
      12 mo
      Centeno (2014)
      • 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.
      Denmark, Sweden, USAII6 (4/2)HandCulture-expanded BMSCPlatelet lysatePercent pain relief

      Modified VAS

      Strength, ROM
      12 mo
      Jo (2014)
      • 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.
      KoreaII18 (3/15)KneeCulture-expanded ADSCn/aWOMAC

      Safety

      Secondary: VAS, KSS, radiographic, histologic evaluation
      6 mo
      Jo (2017)
      • 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.
      KoreaII18 (3/15)KneeCulture-expanded ADSCn/aWOMAC

      KSS

      KOOS

      VAS for pain

      MRI evaluation including cartilage defect size
      24 mo

      Follow-up

      Jo (2014)
      • Diekman B.O.
      • Guilak F.
      Stem cell-based therapies for osteoarthritis: challenges and opportunities.
      Koh (2014)
      • 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.
      KoreaII21 (5/16)KneeSVF/ADSCPRPKOOS

      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)
      • 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.
      VietnamII15 (3/12)KneeSVF/ADSCPRPWOMAC

      Lysolm score

      VAS for pain

      Modified Outerbridge classification
      18 mo
      Pers (2016)
      • 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.
      France, GermanyII18 (8/10)KneeCulture-expanded ADSCn/aVAS for pain

      WOMAC

      Patient Global Assessment

      KOOS

      SAS

      SF-36

      OARSI/OMERACT Responders
      6 mo
      Shapiro (2017)
      • 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.
      USAII25 (7/18)KneeBMAC/BMSCPlatelet-poor bone marrow plasmaVAS for pain

      ICOAP

      WOMAC

      KOOS

      Activity level
      6 mo
      Wakitani (2002)
      • 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.
      JapanII12 (X/X)KneeCulture-expanded BMSCCollagen gel sheetHospital for Special Surgery Knee Rating Scale

      Arthroscopic and Histologic cartilage evaluation
      Mean: 16 months
      Wong (2013)
      • 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.
      SingaporeII28 (15/13)KneeCulture-expanded BMSCHyaluronic acidTegner activity score

      Lysholm score

      IKDC

      ICRS

      MOCART
      2 yrs
      Centeno (2015)
      • Centeno C.
      • Pitts J.
      • Al-Sayegh H.
      • Freeman M.
      Efficacy of autologous bone marrow concentrate for knee osteoarthritis with and without adipose graft.
      USAIII373 (283/126)KneeBMAC/BMSCPRP,

      Platelet lysate
      NPS

      LEFS

      Subjective Improvement Rating Scale

      IKDC
      Varied by outcome, at least 12 mo
      Centeno (2014)
      • 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.
      USAIII681 (516/324)
      Based on number of knees treated.
      KneeBMAC/BMSC ± SVF/ADSCPRP,

      Platelet lysate
      NPS

      LEFS

      Subjective Improvement Rating Scale
      12 mo
      Kim (2015)
      • 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?.
      KoreaIII56 (22/32)
      Based on number of knees treated.
      KneeSVF/ADSCGroup 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)
      • 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.
      KoreaIII26 (11/15)AnkleSVF/ADSCn/aVAS for pain

      AOFAS

      Radiological talar tilt angle

      ICRS grade
      Mean 27.7 ± 2.4 mo

      (Range 24–34 mo)
      Kim (2015)
      • 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.
      KoreaIII40 (14/26)KneeSVF/ADSCInjection 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)
      • Kim Y.S.
      • Lee M.
      • Koh Y.G.
      Additional mesenchymal stem cell injection improves the outcomes of marrow stimulation combined with supramalleolar osteotomy in varus ankle osteoarthritis: short-term clinical results with second-look arthroscopic evaluation.
      KoreaIII31 (15/16)AnkleSVF/ADSCn/aVAS for pain

      AOFAS

      Radiological tibial ankle surface, tibial lateral surface and talar tilt angle

      ICRS grade
      Mean 27.6 ± 5.0 mo
      Koh (2012)
      • 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.
      KoreaIII25 (8/17)KneeSVF/ADSCPRPLysholm score

      Tegner activity scale

      VAS for pain
      Mean 16.4 ± 2.3 mo

      (Range 12–18 mo)
      Ahmad (2014)
      • 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.
      EgyptIV10 (3/7)KneePBSCn/aWOMAC

      6MWD

      MOAKS
      12 mo
      Bansal (2017)
      • 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.
      IndiaIV10 (6/4)KneeSVF/ADSCPRPWOMAC

      6MWD

      X-Ray joint space width

      MRI articular cartilage thickness
      2 yrs
      Buda (2016)
      • 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.
      ItalyIV56 (37/19)AnkleBMAC/

      BMSC
      Autologous platelet-rich fibrinAOFAS

      MOCART
      36 mo
      Centeno (2011)
      • 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.
      USAIV135 (93/42)KneeCulture-expanded BMSCPlatelet lysate or PRPLikert scale for reported pain reliefMean 11.3 mo
      Centeno (2015)
      • 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.
      USAIV34 (27/7)ShoulderBMAC/BMSCPRP,

      Platelet lysate
      DASH

      NPS

      Subjective Improvement Rating Scale
      At least 3 mo
      Davatchi (2011)
      • Davatchi F.
      • Abdollahi B.S.
      • Mohyeddin M.
      • Shahram F.
      • Nikbin B.
      Mesenchymal stem cell therapy for knee osteoarthritis. Preliminary report of four patients.
      IranIV4 (2/2)KneeCulture-expanded BMSCPhysiological serumVAS for pain

      Walking time to pain

      Number of stairs to pain

      Time to gelling pain

      RoM

      Patellar crepitus

      Swelling, Instability
      6 mo
      Davatchi (2016)
      • Davatchi F.
      • Sadeghi Abdollahi B.
      • Mohyeddin M.
      • Nikbin B.
      Mesenchymal stem cell therapy for knee osteoarthritis: 5 years follow-up of three patients.
      IranIV4 (2/2)KneeCulture-expanded BMSCPhysiological serumSame as Davatchi (2011)
      • 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.


      Patient Global Assessment
      5 yrs

      Follow-up Davatchi (2011)
      • 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.
      Emadedin (2012)
      • 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.
      IranIV6 (0/6)KneeCulture-expanded BMSCn/aVAS

      WOMAC

      Walking distance

      Time to gelling

      Patellar crepitus

      RoM

      MRI cartilage assessment
      12 mo
      Emadedin (2015)
      • 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.
      IranIV17(X/X)Ankle (n = 6)

      Hip (n = 5)

      Knee (n = 6)
      Culture-expanded BMSCn/aVAS

      WOMAC

      HHS

      FAOS

      Walking distance

      Lab studies

      MRI analysis
      30 mo
      Fodor (2016)
      • Fodor P.B.
      • Paulseth S.G.
      Adipose derived stromal cell (ADSC) injections for pain management of osteoarthritis in the human knee joint.
      USAIV6 (1/7)
      Based on number of knees treated.
      KneeSVF/ADSCn/aVAS for pain

      WOMAC

      RoM

      Timed up-and-go

      MRI - observational
      1 yr
      Gibbs (2015)
      • 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.
      AustraliaIV4 (2/2)KneeSVF/ADSCPRP, Moderate exercise programKOOS

      Physical function tests: GUG, SCT

      RPE
      12 mo
      Hudetz (2017)
      • 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.
      CroatiaIV17 (12/5)KneeMicrofragmented/ADSCn/aVAS for pain

      dGEMRIC

      IgG Glycans
      12 mo
      Kim (2015)
      • Kim Y.S.
      • Choi Y.J.
      • Koh Y.G.
      Mesenchymal stem cell implantation in knee osteoarthritis: an assessment of the factors influencing clinical outcomes.
      KoreaIV49 (26/29)
      Based on number of knees treated.
      KneeSVF/ADSCFibrin glue productIKDC score

      Tegner activity scale

      Overall surgery satisfaction
      Mean 26.7 ± 3.6 mo (Range 24–36 mo)
      Kim (2016)
      • 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.
      KoreaIV20 (9/15)
      Based on number of knees treated.
      KneeSVF/ADSCFibrin glue productIKDC

      Tegner activity scale

      MOAKS

      MOCART
      Mean 27.9 ± 3.2 mo

      (Range 24–34 mo)
      Koh (2015)
      • 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.
      KoreaIV30 (5/25)KneeSVF/ADSCPRPKOOS

      Lysholm score

      VAS

      Second-look arthroscopy evaluation of cartilage
      24 mo
      Koh (2013)
      • 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.
      KoreaIV18 (6/12)KneeSVF/ADSCPRPWOMAC

      Lysholm score

      VAS for pain

      WORMS
      Mean 24.3 ± 0.8 mo

      (Range 24–26 mo)
      Koh (2014)
      • 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.
      KoreaIV56 (22/34)KneeSVF/ADSCn/aIKDC

      Tegner activity scale

      Patient satisfaction

      Second-look arthroscopy – ICRS
      Mean 26.7 ± 2.5 mo
      Mardones (2017)
      • Mardones R.
      • Jofre C.M.
      • Tobar L.
      • Minguell J.J.
      Mesenchymal stem cell therapy in the treatment of hip osteoarthritis.
      ChileIV10 (7/6)
      Based on number of knees treated.
      HipCulture-expanded BMSCn/aVAS

      WOMAC

      HHS

      VAIL hip score

      Tönnis Classification of Osteoarthritis
      Range 16–40 mo
      Murphy (2017)
      • 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.
      IrelandIV13 (2/11)Thumb – CMC jointBMAC/BMSCTisseelVAS

      RoM

      Kapandji opposition score

      Strength (pinch test)

      DASH

      Grind test
      12 mo
      Oliver (2014)
      • Oliver K.
      • Bayes M.
      • Crane D.
      • Pathikonda C.
      Clinical outcome of bone marrow concentrate in knee osteoarthritis.
      USAIV70 (21/49),

      122 knees
      KneeBMAC/BMSC + SVF/ADSCn/aKOOS

      Adverse events
      180 days
      Orozco (2013)
      • 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.
      SpainIV12 (6/6)KneeCulture-expanded BMSCn/aVAS

      WOMAC

      Lequesne severity index

      SF-36 Quality of Life Questionnnaire

      Poor Cartilage Index – MRI
      12 mo
      Orozco (2014)
      • 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.
      SpainIV12 (6/6)KneeCulture-expanded BMSCn/aVAS

      WOMAC

      Lequesne severity index

      Poor Cartilage Index – MRI
      2 yrs

      Follow-up Orozco (2013)
      • 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.
      Pak (2011)
      • 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.
      KoreaIV2 (0/2)KneeSVF/ADSCPRP, dexamethasone, hyaluronic acidVAS

      Functional rating index

      RoM

      MRI evaluation of cartilage
      3 mo
      Pak (2013)
      • 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.
      KoreaIV74 (X/X)Hip (n = 7)

      Ankle (n = 2)

      Knee (n = 74)
      SVF/ADSCPRP, Hyaluronic acidVAS for pain

      MRI – assessed for tumor formation
      At least 12 mo
      Pak (2016)
      • 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.
      KoreaIV3 (1/2)KneeSVF/ADSCECM, Hyaluronic acid, PRPVAS

      Functional rating Index

      RoM

      MRI cartilage assessment
      18 wks
      Park (2017)
      • 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.
      KoreaIV7 (2/5)KneeAllogeneic, culture-expanded hUCB-MSCsHyaluronic acid hydrogelICRS grade

      VAS for pain

      IKDC

      Histological findings
      7 yrs
      Pintat (2017)
      • 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.
      FranceIV19 (10/9)PatellofemoralSVF/ADSCPRPWOMAC

      MRI – ICRS-like classification
      12 mo
      Russo (2017)
      • Russo A.
      • Condello V.
      • Madonna V.
      • Guerriero M.
      • Zorzi C.
      Autologous and micro-fragmented adipose tissue for the treatment of diffuse degenerative knee osteoarthritis.
      ItalyIV30 (21/9)KneeMicrofragmented/ADSCn/aVAS for pain

      KOOS

      IKDC - subjective

      Tegner Lysholm Knee
      12 mo
      Soler (2016)
      • 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.
      SpainIV15 (6/9)KneeCulture-expanded BMSCn/aVAS for pain

      WOMAC

      HAQ, pain subscale

      SF-36

      Lequesne functional index

      MRI T2 mapping
      12 mo
      Turajane (2013)
      • 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.
      ThailandIV5 (1/4)KneePBSCHyaluronic acid, GFA (PRP, hG-CSF)WOMAC

      KOOS
      6 mo
      Bui (2014)
      • 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.
      VietnamIV21 (X/X)KneeSVF/ADSCPRPVAS for pain

      Lysholm score

      MRI cartilage assessment
      8.5 mo
      Varma (2010)
      • Varma H.S.
      • Dadarya B.
      • Vidyarthi A.
      The new avenues in the management of osteo-arthritis of knee - stem cells.
      IndiaIV50 (X/X)KneeBMAC/BMSCn/aVAS

      OAOS
      6 mo
      Wakitani (2011)
      • 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.
      JapanIV26 (X/X)KneeCulture-expanded BMSCCollagen gel sheetAdverse events: tumor development and infectionMean: 75 mo
      Wei (2011)
      • 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.
      USAIV23 (17/6)KneeBMAC/BMSCPRPWOMAC

      VAS for pain

      Patient Global Assessment

      50 foot walk pain

      Physician Global Assessment
      12 mo
      Yokota (2017)
      • 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.
      JapanIV13 (4/22)
      Based on number of knees treated.
      KneeSVF/ADSCn/aVAS for pain

      JKOM

      WOMAC
      6 mo
      Centeno (2008)
      • 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.
      USAV1(0/1)KneeCulture-expanded BMSCAutologous whole-marrow, platelet lysate, dexamethasoneModified VAS

      Functional Rating Index

      ROM

      MRI quantitative volume analysis
      3 mo
      Centeno (2008)
      • 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.
      USAV1(1/0)KneeCulture- expanded BMSCHyoluronate sodium, autologous whole-marrow, platelet lysate, dexamethasoneModified VAS

      Functional Rating Index

      ROM

      MRI quantitative volume analysis
      3 mo
      Centeno (2008)
      • 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.
      USAV1 (1/0)KneeCulture- expanded BMSCAutologous marrow-derived nucleated cells, platelet lysate, dexamethasoneModified VAS

      Functional rating index

      ROM

      MRI quantitative volume analysis
      6 mo
      Mehrabani (2016)
      • 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.
      IranV1 (0/1)KneeCulture-expanded BMSCn/aWOMAC

      VAS for pain

      Walking distance

      Time to gelling

      Patellar crepitus

      RoM

      MRI cartilage assessment
      12mo
      Pak (2017)
      • 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.
      KoreaV1 (0/1)HipSVF/ADSCECM, Hyaluronic acid, PRPVAS 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.
      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
      • 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.
      • Oliver K.
      • Bayes M.
      • Crane D.
      • Pathikonda C.
      Clinical outcome of bone marrow concentrate in knee osteoarthritis.
      . 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
      Randomized processConfoundingParticipant selectionIntervention classificationDeviations from intended interventionMissing dataOutcomes measurementSelection of reported resultOverall
      Garay-Mendoza (2017)
      • 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.
      LowLowLowLowLowLow
      Gupta (2016)
      • 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.
      LowLowLowLowLowLow
      Lamo-Espinosa (2016)
      • 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).
      LowLowLowLowLowLow
      Turajane (2017)
      • 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.
      LowLowLowLowLowLow
      Vega (2015)
      • 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.
      LowLowLowLowLowLow
      Centeno (2014)
      • 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.
      ModerateLowLowLowModerateModerateLowModerate
      Jo (2014)
      • 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.
      ModerateLowModerateLowLowModerateLowModerate
      Jo (2017)
      • 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.
      ModerateLowModerateLowModerateModerateLowModerate
      Koh (2014)
      • 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.
      LowLowSome concernsLowLowSome concerns
      Nguyen (2016)
      • 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.
      LowLowLowLowLowModerateModerateModerate
      Pers (2016)
      • 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.
      LowLowModerateModerateModerateModerateLowModerate
      Shapiro (2017)
      • 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.
      LowLowLowSome concernsLowSome concerns
      Wakitani (2002)
      • 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.
      Some concernsLowSome concernsSome concernsSome concernsHigh
      Wong (2013)
      • 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.
      Some concernsLowLowSome concernsSome concernsHigh
      NI = no information

      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
      • 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)
      • 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 siteBiologic adjuvantInjection procedureNumber of injected MSCsFollow-upNumber of injections
      Garay-Mendoza (2017)
      • 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.
      BMAC/BMSC: iliac crestOutpatient

      SQ G-CSF x 3 days
      Intra-articular injection of 10 mL concentrate without radiographic guidance10 ml concentrate

      TNC: 302.2 × 107

      Mononuclear: 67.33 × 107

      CD34+: 20.56 × 106
      1 wk, 1, 6 mo1
      Gupta (2016)
      • 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.
      Allogeneic CE BMSC: from 3 healthy volunteersPLASMALYTE-A

      Pre: Hydrocortisone and pheniramine maleate

      Post: Hyaluronic acid
      Pre-medication of hydrocortisone and pheniramine maleate. Intra-articular injection without radiographic guidance followed by HA4 dose levels: 25, 50, 75, 150 × 10612 mo1
      Lamo-Espinosa (2016)
      • 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).
      CE BMSC: iliac crestHyaluronic acidIntra-articular injection without radiographic guidanceLow-dose: 10 × 106

      High-dose: 100 × 106
      3, 6, 12 mo2
      Turajane (2017)
      • 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.
      PBSCHyaluronic 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 mo3
      Vega (2015)
      • 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.
      Allogeneic culture-expanded BMSC: iliac crestn/aIntra-articular injection without radiographic guidance40 × 1068 days, 3, 6, 12 mo1
      Centeno (2014)
      • 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.
      CE BMSC: iliac crestPlatelet lysateIntra-articular injection with radiographic and fluoroscopic guidance5.76 × 1063, 6, & 12 mo1
      Jo (2014)
      • 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.
      CE ADSC: SQ abdominal fatn/aIntra-articular injection with 3 mL salineLow-dose: 10 × 106

      Mid-dose: 50 × 106

      High-dose: 100 × 106
      6 mo1
      Jo (2017)
      • 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.
      CE ADSC: SQ abdominal fatn/aIntra-articular injection with 3 mL salineLow-dose: 10 × 106

      Mid-dose: 50 × 106

      High-dose: 100 × 106
      12, 24 mo1
      Koh (2014)
      • 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.
      SVF/ADSC: SQ buttocksPRPIntra-articular arthroscopic-guided injection followed by open-wedge HTO120 ml of SVF

      Estimated

      8.5% of 4.83 × 107 SVF cells

      (4.11 × 106)
      Mean 24.2 ± 4.7 mo1
      Nguyen (2016)
      • 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.
      SVF/ADSC: SQ abdominal fatPRPIntra-articular injection with 5 ml SVF + PRP107 SVF cells/ml1, 6, 12, 18 mo1
      Pers (2016)
      • 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.
      CE ADSC: SQ abdominal fatn/aIntra-articular injection with ultrasound guidanceLow-dose: 2 × 106

      Mid-dose: 10 × 106

      High-dose: 50 × 106
      6 mo1
      Shapiro (2017)
      • 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.
      BMAC/BMSC: iliac crestPlatelet-poor bone marrow plasmaUltrasound guided intra-articular injection of 5 ml BMAC with 10 ml platelet-poor bone marrow plasmaMedian of 3.4 × 104 MSCs and 4.62 × 106 hematopoietic stem cells1 wk, 3 mo, 6 mo1
      Wakitani (2002)
      • 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.
      CE BMSC: iliac crestCollagen gel sheetHTO followed by collagen cell sheet with cells implanted1.3 × 107Mean: 16 months1
      Wong (2013)
      • 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.
      CE BMSC: iliac crestHyaluronic acidHTO and microfracture followed 3 weeks later with intra-articular injection with 2 ml HA1.46 ± 0.29 × 106every 6 weeks for 6 mo, 1, 2 yrs1 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.

      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
      • 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.
      • 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.
      • 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.
      • 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 groupsOutcomes measuresMSC group scores: Baseline vs Final F/U (x ± SD)MSC-groups significant improvement from baselineComparison group scores: Baseline vs Final F/USignificant improvement with comparison
      Garay-Mendoza (2017)
      • 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.
      Acetaminophen 500 mg every 8 h for 6 monthsVAS5.27 ± 2.196 vs 0.92 ± 1.294.32 ± 2.35 vs 4.64 ± 2.43Yes, 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 ± 9.456.93 ± 17.89 vs 72.96 ± 15.04Yes, P < 0.0001
      SafetySwelling, pain, stiffnessSwelling, pain, stiffness
      Gupta (2016)
      • 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.
      Dose-escalation cohorts

      Placebo: injection of PLASMA-LYTE A
      VASLow 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 sizePlacebo 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
      ICOAPLow 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 sizePlacebo 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
      WOMACLow 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 sizePlacebo 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/APlacebo 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
      SafetyPain and swelling

      One serious event: synovial effusion
      N/APain and swellingN/A
      Lamo-Espinosa (2016)
      • 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).
      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/A5 (3,7) vs 4 (3,5)With low dose cohort:

      Yes, P = 0.005

      With high dose cohort:

      Yes, P < 0.009
      WOMACLow 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/AMRI (WORMS): no change in joint damage

      X-Ray: reduction in joint space width
      N/A
      Knee Flexion and Extension MeasurementsFlexion 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
      SafetyNo adverse events besides mild painN/ANo adverse events besides mild painN/A
      Turajane (2017)
      • 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.
      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 monthsCohort 1:0 patients need joint replacement

      Cohort 2:0 patients need joint replacement
      N/A3 need joint replacementYes, P < 0.033
      WOMACCohort 1: 218.5 vs 52

      Cohort 2: 212.2 vs 75
      Yes, P < 0.0001

      Yes, P < 0.0001
      215.3 vs 126.8With cohort 1:

      Yes, P < 0.001

      With cohort 2:

      Yes, P < 0.001
      Vega (2015)
      • 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.
      Placebo:

      HA alone
      VASSE54 ± 7 vs 33 ± 6N/A64 ± 7 vs 51 ± 8Yes, P < 0.005
      WOMACSE41 ± 3 vs 28 ± 5N/A45 ± 3 vs 41 ± 6Yes, P < 0.005
      Lequesne scoreSE39 ± 4 vs 30 ± 3N/A45 ± 4 vs 42 ± 5Yes, P < 0.005
      SF-12 PCS40 ± 9 vs 45 ± 11No, P > 0.0535 ± 8 vs 40 ± 8No, P > 0.05
      SF-12 MCS54 ± 10 vs 51 ± 12No, P > 0.0549 ± 9 vs 47 ± 11No, P > 0.05
      MRI (PCI)Decreased significantly by 1 yearYes, P < 0.05Does not drop significantly by 1 yearNo, P > 0.05
      SafetyInflammation during first 7 daysN/AInflammation during first 7 daysN/A
      Centeno (2014)
      • 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.
      Untreated procedure candidates

      (No placebo)
      −100% to +100% pain relief scale60% improvement19 % improvementYes, P = 0.03
      VAS63% improvement (5.2 vs 2.0)
      Jo (2014)
      • 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.
      Dose-escalation cohorts

      (No placebo)
      WOMACSELow 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/AN/A
      SafetyNo treatment-related adverse eventsN/AN/AN/A
      VASLow 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/AN/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/AN/A
      N/AN/A
      Jo (2017)93Dose-escalation cohorts

      (No placebo)
      WOMACLow 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/AN/A
      VASLow 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/AN/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/AN/A
      Koh (2014)
      • 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.
      PRP aloneVAS44.3 ± 5.7 vs 10.2 ± 5.7N/A45.4 ± 7.1 vs 16.2 ± 4.6Yes, P < 0.001
      KOOS pain scale

      KOOS symptom scale
      81.2 ± 6.9 vs N/A

      82.8 7.2 vs N/A
      N/A74.0 ± 5.7

      75.4 ± 8.5
      Yes, P < 0.001

      Yes, P = 0.006
      Lysholm score55.7 ± 11.5 vs 84.7 ± 16.2N/A56.7 ± 12.2 vs 80.6 ± 13.5No, 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/AVarus 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)
      • 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.
      Arthroscopic microfracture aloneWOMAC42.87 ± 16.29 vs 17.33 ± 14.91N/A47.37 ± 17.13 vs 37.08 ± 21.45Yes, P < 0.05
      Lysolm score53.47 ± 14.56 vs 84.73 ± 19.54N/A64.13 ± 10.19 vs 65.17 ± 14.74Yes, P < 0.05
      VAS for pain1.60 ± 0.83 vs 3.47 ± 0.74Yes, P < 0.052.67 6 0.62 vs 1.40 6 0.51Yes, P < 0.05
      Modified Outerbridge classification3.33 ± 0.97 vs 2.93 ± 0.88N/A2.67 ± 1.35 vs 4.02 ± 1.08No, P > 0.05

      Note: scores increase in placebo, decrease if treated
      Pers (2016)
      • 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.
      Dose-escalation cohorts

      (No placebo)
      SafetyOnly one severe adverse event

      (UA in a patient with multiple risk factors)
      N/AN/AN/A
      VASLow 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/AN/A
      WOMACLow 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/AN/A
      KOOSLow 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/AN/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)
      • 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.
      Saline into each patient's contralateral knee. Patient blinded to knee with treatment vs placebo.VAS for pain3.1 vs 1.5Yes, P = 0.0012.9 vs 0.8No, P = 0.44
      ICOAP32 vs 16Yes, P = 0.000532 vs 9No, P = 0.54
      Activity levelNo/mild limits: 6 vs 15

      Moderate limits: 13 vs 9

      Severe/extreme limits: 6 vs 1
      Yes, P = 0.0003No/mild limits: 8 vs 17

      Moderate limits: 11 vs 5

      Severe/extreme limits: 6 vs 3
      No, P = 0.51
      Wakitani (2002)
      • 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.
      Cell-free collagen gel-sheet implantationHSS Knee Rating Scale65.0 ± 6.7 vs 81.3 ± 8.6Yes, P = 0.002966.3 ± 10.5 vs 79.2 ± 8.7No, P > 0.05
      Arthroscopic/histologic cartilage evaluation9.8 ± 2.0 vs 15.4 ± 1.47.5 ± 2.2 vs 10.0 ± 6.1

      8.0 ± 0.9 vs 11.3 ± 2.3
      Yes, P < 0.05
      Wong (2013)
      • 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.
      HTO + HA aloneLysholm scorei41.9 ± 19.2 vs N/A

      Improvement of 7.61
      Yes, P = 0.01650.4 ± 23.0 vs N/AYes, P = 0.016
      IKDCi

      33.9 ± 11.4 vs N/A

      Improvement of 7.65
      Yes, P = 0.00136.0 ± 13.7 vs N/AYes, P = 0.001
      Radiographic (MOCART)62.32 ± 17.5643.21 ± 13.55Yes, 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.
      Of the ten level I and II evidence studies that measured VAS for pain, patients in all of the studies exhibited VAS score improvements
      • 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.
      • 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.
      • 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).
      • 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.
      • 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.
      • 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.
      • 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.
      • 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.
      • 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.
      • 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
      • 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.
      • 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.
      • 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).
      • 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.
      • 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.
      • 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.
      • 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.
      • 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.
      • 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.
      • 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
      • 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
      • 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
      • 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.
      • 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)
      • 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
      • 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.
      • 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.
      • 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.
      • 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).
      • 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.
      • 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.
      • 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.
      • 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.
      • 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.
      • 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.
      • 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
      • 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.
      • 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
      • 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.
      • 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.
      • 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.
      • 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
      • 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.
      • 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.
      • 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).
      • 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.
      • 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.
      • 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
      • 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.
      • 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.
      • 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).
      • 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.
      • 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.
      • 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
      • 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.
      • 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).
      • 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.
      • 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.
      • 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
      • 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
      • 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
      • 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.
      • 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
      • 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
      • 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
      • 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.
      • 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
      • 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
      • 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
      • 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
      • 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.
      • 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
      • 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
      • 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.
      • 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
      • 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.
      • 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.
      • 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
      • 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.
      • 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.
      • 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
      • 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
      • 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
      • 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.
      , HSS Knee Rating Scale
      • 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.
      , and second look arthroscopy and histology
      • 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.
      .

      Discussion

      Stem cell therapy appears to alleviate the symptoms of osteoarthritis and potentially halt cartilage damage. Although studies detailing the therapeutic effect of MSCs in osteoarthritic patients are limited in number and quality, the majority of available literature has reported positive results. The studies, however, are inconsistent in their methodology and few studies are levels I or II evidence. Over half (57%) of evidence available is level IV evidence which consists of therapeutic case series without comparative groups
      • Marx R.G.
      • Wilson S.M.
      • Swiontkowski M.F.
      Updating the assignment of levels of evidence.
      . Nonetheless, analysis of the articles' results suggest an association between MSC therapy and OA symptomatic and radiologic improvement. There has been some conflicting evidence, however, in the longterm maintenance of positive results. In a two-year follow-up, Jo et al.
      • Park Y.B.
      • Ha C.W.
      • Lee C.H.
      • Yoon Y.C.
      • Park Y.G.
      Cartilage regeneration in osteoarthritic patients by a composite of allogeneic umbilical cord blood-derived mesenchymal stem cells and hyaluronate hydrogel: results from a clinical trial for safety and proof-of-concept with 7 years of extended follow-up.
      found that although WOMAC, VAS, KSS and KOOS improved from baseline, these scores plateaued or decreased after one year. To the contrary, Nguyen et al.
      • 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.
      looked at WOMAC, Lysholm score, and VAS and found that both treatment and placebo groups significantly improved from baseline (P < 0.05), but it was not until 18 months that the treated group had significantly improved scores compared to placebo (P < 0.05). This supports the need for studies that assess longer term clinical outcomes in order to better understand the intervention's sustainability. This also draws attention to the need for protocol consistency since it is difficult to formulate conclusions from these longterm studies when different forms of MSC administration are used, as demonstrated by these examples, respectively
      • 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.
      • Park Y.B.
      • Ha C.W.
      • Lee C.H.
      • Yoon Y.C.
      • Park Y.G.
      Cartilage regeneration in osteoarthritic patients by a composite of allogeneic umbilical cord blood-derived mesenchymal stem cells and hyaluronate hydrogel: results from a clinical trial for safety and proof-of-concept with 7 years of extended follow-up.
      .
      MSC therapy caused few adverse effects in studies that investigated treatment safety. Two serious adverse events were recorded in the levels I and II evidence including a synovial effusion requiring overnight observation
      • 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.
      and unstable angina in a patient with multiple risk factors three months after injection.
      • 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.
      Other adverse events recorded included pain and swelling. Vega et al.
      • 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.