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Background:
Systematic Review

Methodological Flaws in Meta-Analyses of Clinical Studies on the Management of Knee Osteoarthritis with Stem Cells: A Systematic Review

by
Christoph Schmitz
1,*,
Christopher Alt
2,3,4,
David A. Pearce
4,5,6,
John P. Furia
7,
Nicola Maffulli
8,9,10 and
Eckhard U. Alt
2,3,6,11
1
Chair of Anatomy II, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians University, 80336 Munich, Germany
2
Isar Klinikum, General Management, 80331 Munich, Germany
3
InGeneron Inc., Houston, TX 77054, USA
4
Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57105, USA
5
Sanford Health, Sioux Falls, SD 57117, USA
6
Sanford Research, Sioux Falls, SD 57105, USA
7
SUN Orthopedics of Evangelical Community Hospital, Lewisburg, PA 17837, USA
8
Department of Musculoskeletal Disorders, Faculty of Medicine and Surgery, University of Salerno, 84084 Fisciano, Italy
9
Centre for Sports and Exercise Medicine, Barts and the London School of Medicine and Dentistry, Mile End Hospital, Queen Mary University of London, London E1 2AD, UK
10
School of Pharmacy and Bioengineering, Guy Hilton Research Centre, Keele University School of Medicine, Stoke on Trent ST4 7QB, UK
11
Heart and Vascular Institute, Department of Medicine, Tulane University Health Science Center, New Orleans, LA 70112, USA
 
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*
Author to whom correspondence should be addressed.
Cells 2022, 11(6), 965; https://doi.org/10.3390/cells11060965
Submission received: 17 February 2022 / Revised: 8 March 2022 / Accepted: 9 March 2022 / Published: 11 March 2022
(This article belongs to the Special Issue Regeneration of Tissue with Mesenchymal Stem Cells)
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Abstract

:
(1) Background: Conclusions of meta-analyses of clinical studies may substantially influence opinions of prospective patients and stakeholders in healthcare. Nineteen meta-analyses of clinical studies on the management of primary knee osteoarthritis (pkOA) with stem cells, published between January 2020 and July 2021, came to inconsistent conclusions regarding the efficacy of this treatment modality. It is possible that a separate meta-analysis based on an independent, systematic assessment of clinical studies on the management of pkOA with stem cells may reach a different conclusion. (2) Methods: PubMed, Web of Science, and the Cochrane Library were systematically searched for clinical studies and meta-analyses of clinical studies on the management of pkOA with stem cells. All clinical studies and meta-analyses identified were evaluated in detail, as were all sub-analyses included in the meta-analyses. (3) Results: The inconsistent conclusions regarding the efficacy of treating pkOA with stem cells in the 19 assessed meta-analyses were most probably based on substantial differences in literature search strategies among different authors, misconceptions about meta-analyses themselves, and misconceptions about the comparability of different types of stem cells with regard to their safety and regenerative potential. An independent, systematic review of the literature yielded a total of 183 studies, of which 33 were randomized clinical trials, including a total of 6860 patients with pkOA. However, it was not possible to perform a scientifically sound meta-analysis. (4) Conclusions: Clinicians should interpret the results of the 19 assessed meta-analyses of clinical studies on the management of pkOA with stem cells with caution and should be cautious of the conclusions drawn therein. Clinicians and researchers should strive to participate in FDA and/or EMA reviewed and approved clinical trials to provide clinically and statistically valid efficacy.

1. Introduction

Osteoarthritis (OA) is the most common cause of pain and disability worldwide, especially in the elderly population [1,2]. The hip and knee joints are most commonly affected, and women are more frequently affected than men [3,4]. Osteoarthritis is characterized by cartilage and meniscus degeneration, subchondral bone remodeling, synovial membrane inflammation, and infrapatellar fat pad inflammation and fibrosis [4,5].
There is no cure for OA, despite its high prevalence and deleterious impact on the quality of life of affected individuals [1,2]. The currently available therapeutic measures aim to relieve pain and maximize functional capacity and quality of life, while minimizing any adverse effects from drugs and invasive interventions [6]. Patients suffering from primary knee OA (pkOA) often report refractory, severe, and disabling pain and are eventually referred for partial or total arthroplasty [7].
Intra-articular (i.a.) injection of platelet-rich plasma (PRP), corticosteroids (CS), and hyaluronic acid (HA) is commonly used to manage pkOA [8,9]. These injections can easily be administered, fewer treatment sessions are necessary compared with other treatments, and the treatment adherence of patients is relatively easy to achieve (except for repeated injections). According to the Osteoarthritis Research Society International (OARSI) guidelines, i.a. injection of CS and HA (but not of PRP) are among the recommended treatments for pkOA, dependent upon comorbidity status [10]. A recent meta-analysis of the efficacy and safety of i.a. injection of CS and HA for pkOA concluded that both therapies are relatively safe and lead to comparable improvements in knee function [11]. According to such meta-analysis, better short-term effects (up to one month) are obtained with CS than with HA, and better long-term effects (up to six months) are achieved with HA than with CS [11]. On the other hand, i.a. injection of HA causes more topical adverse effects than i.a. injection of CS [11].
Over the last two decades, various studies (summarized in Table S1 in Supplementary Material; refs [12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195]) have proposed the management of pkOA with different types of stem cells, which can be derived from many different sources (autologous, adipose-derived regenerative cells; autologous, adipose-derived stem cells (obtained by culturing ADRCs); autologous stem cells isolated from infrapatellar fat pad; allogeneic, adipose-derived stem cells; autologous, micro-fragmented fat (from liposuction); autologous, centrifuged liposuction liquid; autologous bone marrow concentrate; autologous, bone-marrow-derived mesenchymal stem cells; allogeneic, bone-marrow-derived mesenchymal stromal cells; autologous, matrix-induced mesenchymal stem cells from synovia; allogeneic chondrocytes that overexpress transforming growth factor beta; allogeneic, human umbilical cord-derived MSCs; allogeneic, placental mesenchymal stem cells; autologous, activated peripheral blood stem cells; and allogeneic amniotic fluid). It is beyond the scope of this study to provide a comprehensive description of the different motivations behind the use of these different types of stem cells and their specific advantages and disadvantages. A general discussion of the advantages of autologous stem cells over allogeneic stem cells, as well as of the advantages of uncultured stem cells over cultured stem cells, is provided in, e.g., [196].
In general, there are various motivations behind the idea to manage pkOA with stem cells (summarized in, e.g., [197]). The most important ones are the findings that stem cells can be converted into chondrocytes in vitro, as well as that transplantation of stem cells prevented or improved experimental osteoarthritis in animal models (summarized in, e.g., [197]). On the other hand, it has remained unclear whether (and if so, to what extent) implanted stem cells transform to chondrocytes, replace missing cells, and thereby repair the cartilage (note that, in principle, this could only be achieved with autologous stem cells but not with allogeneic stem cells [196]). Alternatively, stem cells may suppress synovial activation and indirectly ameliorate cartilage damage by establishing a repair microenvironment and stimulating tissue repair through the recruitment of local endogenous stem cells [197].
As outlined in detail in Section 2 below, we identified 19 meta-analyses by means of a systematic literature search according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [198]. These papers were all published between January 2020 and July 2021 [199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217]. Unfortunately, the conclusions of these meta-analyes are inconsistent. Specifically, these meta-analyses demonstrated (i) the efficacy of treating pkOA with stem cells [199,200,201,202,203,204]; (ii) the superiority of autologous stem cells derived from adipose tissue over other types of stem cells in the management of pkOA [205,206,207,208,209]; (iii) the efficacy of treating pkOA with autologous, adipose-derived stem cells, without comparison with other types of stem cells [210,211]; (iv) the superiority of autologous, bone-marrow-derived stem cells over autologous, adipose-derived stem cells in the management of pkOA [212]; (v) the efficacy of treating pkOA with autologous, bone-marrow-derived stem cells, without comparison with other types of stem cells [213]; (vi) the efficacy of treating pkOA with allogeneic stem cells [214]; (vii) the efficacy of treating pkOA with stem cells only in conjunction with surgery [215]; and (viii) the lack of efficacy of treating pkOA with stem cells [216,217] (summarized in Table S2).
To determine the reasons for these inconsistent conclusions, we performed a comprehensive assessment of all clinical studies included in these 19 meta-analyses [199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217]. Furthermore, we determined whether a separate meta-analysis based on an independent, systematic assessment of studies on the management of pkOA with stem cells would reach a different conclusion.

2. Materials and Methods

PubMed, Web of Science, and the Cochrane Library were searched for “knee osteoarthritis stem cell*”, “knee osteoarthritis stromal vascular fraction”, and “knee osteoarthritis SVF” from the days of inception of these databases until 7 August 2021 according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [198] guidelines. Duplicates were excluded. This search strategy found many more clinical studies than evaluated in the 19 assessed meta-analyses [199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217].
The strategy of the first assessment of the identified publications is summarized in Figure 1.
In the first step, for each identified publication, it was determined by reading the title and abstract whether the publication represented a meta-analysis of clinical studies on the management of pkOA with stem cells and was published in 2020 or 2021. This was independently undertaken by C.S. and C.A. Results were compared and discussed until agreement was achieved. Afterwards, all studies included in the identified meta-analyses that reported the management of pkOA with stem cells were classified with regard to the type of study as summarized in Table 1 and Table 2, as well as with regard to the type of stem cells used as summarized in Table 3. Thereafter, all identified meta-analyses were classified by C.S. and C.A. with regard to the type of meta-analysis performed as summarized in Table 4.
Then, two types of meta-analysis were excluded from further assessment: those in which only the endpoints of the same patients before and after treatment were compared (four meta-analyses) (Class 2 in Table 4) and those in which the vast majority (>80%) of clinical studies included addressed management of pkOA with different modalities than stem cells (three meta-analyses) (Class 3 in Table 4).
Afterwards, the quality of each sub-analysis performed in the remaining 12 meta-analyses (Class 1 in Table 4) was assessed by C.S. and C.A. according to the quality criteria outlined in Table 5.
The strategy of the second assessment of the identified publications is summarized in Figure 2. In the first step, C.S. and C.A. excluded reviews and investigations that did not represent clinical studies on the management of pkOA with stem cells. Then, each study identified in this search was classified with regard to the type of study as summarized in Table 1 and Table 2 and with regard to the type of stem cells used as summarized in Table 3. Furthermore, it was determined which analyses could be performed that fulfilled all quality criteria summarized in Table 5. All this was undertaken by C.S. and C.A.

3. Results

3.1. Assessment of Published Meta-Analyses

A total of 56 clinical studies [12,13,14,15,16,17,18,19,20,21,22,23,24,25,28,29,30,32,37,38,39,40,46,47,50,51,52,53,55,56,62,63,64,65,67,69,81,82,98,99,100,105,110,111,112,115,118,119,137,156,157,161,218,219,220,221] was included in the 19 assessed meta-analyses; details of these 56 clinical studies are provided in Table S3. Classification of these 56 studies with regard to the type of study is summarized in Table 1 and Table 2. Two of these 56 studies [220,221] (3.6%) could not be evaluated because they were not listed in PubMed, Web of Science, and the Cochrane Library, nor are they listed on Google Scholar.
Of note, four of the 54 studies [156,157,161,218] that could be evaluated (7.4%) did not address pkOA but rather, respectively, focal chondral, osteochondral, meniscal chondral, or meniscal lesions. Furthermore, only 29 of the 54 studies that could be evaluated (53.7%) were randomized controlled trials (RCT); the other studies were RCTs with the contralateral knee as internal control (3/54 = 5.6%), prospective cohort studies (7/54 = 13.0%), retrospective cohort studies (2/54 = 3.7%), and case series without control groups (13/54 = 24.1%) (Table 2).
Thirteen different types of stem cells (eight were autologous cell types, and five were allogeneic cell types) were applied in the 54 studies that could be evaluated (Table 3). The most frequently applied cell types were autologous, adipose-derived stem cells (ADSCs) (11/54 = 20.4%), autologous, bone-marrow-derived mesenchymal stromal cells (BM-MSCS) (10/54 = 18.5%), autologous, adipose-derived regenerative cells (ADRCs) (9/54 = 16.7%), and autologous bone marrow aspirate concentrate (BMAC) (7/54 = 13.0%). In one study [219], no cells but allogeneic amniotic fluid were applied.
Each of the 19 assessed meta-analyses included an average number of 9.3 ± 4.6 (mean ± standard deviation) studies (median, 8; range, 2–18). Conversely, each study listed in Table S3 was included in an average of 3.1 ± 3.5 of the 19 assessed meta-analyses (median, 2; range, 1–15). Only 9 of the 56 studies (16.0%) were included in five or more of the 19 assessed meta-analyses, whereas 26 of the 56 studies (46.4%) were included in only one of the 19 assessed meta-analyses. None of the 56 studies were included in all assessed meta-analyses; the most frequently included study, i.e., [20], was an RCT in which injection of allogeneic BM-MSCs was compared with injection of HA (considered in 15 of the 19 assessed meta-analyses).
In four of the 19 assessed meta-analyses [202,207,210,212], subjective (self-reported pain and function scores) and objective (cartilage measurements) endpoints of the same patients before and after treatment were analyzed. Since this approach cannot rule out the possibility that all reported and measured effects were based on the placebo effect in the management of pkOA [222,223,224], these meta-analyses were excluded from further assessment.
In the three network meta-analyses, respectively, only two [217], three [204], and six [211] studies on the management of pkOA with stem cells were included, but, respectively, 41 [217], 22 [204], and 37 [211] studies addressing the management of pkOA without injection of stem cells were included. Since this approach does not at all reflect the literature that is actually available on the management of pkOA with stem cells (c.f. Table S1), these network meta-analyses were also excluded from further assessment.
In the remaining 12 meta-analyses [199,200,201,203,205,206,208,209,213,214,215,216], a total of 157 sub-analyses were performed; details of these 157 sub-analyses and individual assessment according to the quality criteria listed in Table 5 are provided in Tables S4–S15. The absolute and relative numbers of sub-analyses that fulfilled, respectively, 0/1/2/3/4/5/6/7/8 of the quality criteria outlined in Table 5 were 0/0/2/3/9/18/94/30/1 (or 0%/0%/1.3%/1.9%/5.7%/11.5%/59.9%/19.1%/0.6%, respectively).
The two sub-analyses which fulfilled only 2 of the 8 quality criteria outlined in Table 5 are listed in Table S7; they compared the following studies with respect to the VAS pain score at three months and six months post treatment: a study in which the management of pkOA was performed using allogeneic amniotic fluid [219], a RCT in which the application of allogeneic ADSCs was compared with placebo treatment [16] (study considered two times because of two different doses of stem cells), a RCT in which the application of autologous BM-MSCs plus HA injection was compared with HA injection alone [53] (this study was also considered two times because of two different doses of stem cells), and a study in which the application of autologous BMC plus platelet-poor plasma injections was compared with a placebo treatment, with the contralateral knee as internal control [62].
The only sub-analysis fulfilling all quality criteria outlined in Table 5 is listed in Table S12, and compared the following studies with respect to categorical data (worse/not worse) of different MRI evaluations, which were categorical structures with different scales and, thus, converted to categorical data by the authors of this meta-analysis [213]: a RCT in which the management of pkOA with allogeneic placental mesenchymal stem cells was compared with placebo treatment [17], and a RCT in which the management of pkOA with allogeneic ADSCs was also compared with placebo treatment [16].

3.2. Systematic Assessment of Clinical Studies on Treatment of Primary Knee Osteoarthritis with Stem Cells

Our independent literature search yielded 2912 publications, of which 174 described clinical studies with a total number of n = 7146 patients treated with different types of stem cells (treatment groups). The other 2738 publications were duplicates (n = 858) or addressed topics other than the management of pkOA with stem cells (n = 681), reviews of the literature (n = 476), animal studies (n = 329), in vitro studies (n = 285), commentaries (n = 35), combined animal and in vitro studies (n = 26), conference abstracts (n = 17), study protocols (n = 11), animal studies on different topics (n = 6), reviews of different topics (n = 5), position statements (n = 4), errata (n = 3), and retraction notes (n = 2). Eight of the studies listed in Table S3 [12,15,22,25,50,55,112,156] were not found in this literature search, as well as one study [179] that was mentioned but not used in the sub-analyses performed in one of the assessed meta-analyses [199]. In these nine additional studies, a total number of n = 532 patients was treated with different types of stem cells (treatment groups). Accordingly, the combined literature search (all assessed meta-analyses and the literature search outlined in Figure 2) yielded a total of 183 studies, with a total number of n = 7678 patients. Details of these 183 studies are provided in Table S1. Categorization of these studies with respect to treatment and control treatment is provided in Table 6, with respect to the type of study in Table 7 and with respect to the types of stem cells used in Table 8. Results of the corresponding combined three-step categorization are summarized in Table 9.
Most of the 183 studies listed in Table S1 were performed using autologous BMAC (38 studies comprising a total of 2905 patients, among them 2588 patients with pkOA), followed by autologous ADRCs (36 studies; 1608 patients; 1568 with pkOA), autologous BM-MSCs (34 studies; 468 patients; 385 patients with pkOA), autologous ADSCs (22 studies; 368 patients; 346 patients with pkOA), micro-fragmented fat from liposuction (MFF) (21 studies; 1489 patients with pkOA), peripheral blood-derived MSCs (8 studies; 183 patients with pkOA; 54 patients with pkOA), and other cell types (24 studies; 657 patients; 430 patients with pkOA). It is of note that in none of these 183 studies was a serious adverse event after application of stem cells reported.
Management of pkOA with stem cells was performed on a total of n = 6860 patients in 143 of the 183 studies (Categories I–V in Table 6). The remaining 40 clinical studies (including a total of 818 patients) addressed, respectively, focal chondral, osteochondral, meniscal chondral, or meniscal lesions (Category VI in Table 6), pathologies which are not addressed in the present setting.
In 65 of these 143 clinical studies on the management of pkOA, treatment with stem cells was compared to sham treatment or another treatment (RCTs or prospective or retrospective two- or three-cohort studies, respectively) (Categories I–IV in Table 6). On the other hand, the management of pkOA with i.a. injection of stem cells as the sole treatment (not considering rehabilitation) was performed in only 38 of these 65 studies (Categories I-III in Table 6), and i.a. injection of, respectively, saline or sham treatment was only performed in 8 of these 38 studies (Category I in Table 6).
According to the quality criteria of the meta-analyses of studies on the management of pkOA with stem cells outlined in Table 5, it would generally be possible to perform the sub-analyses shown in Table 10. However, MFF must not be confused with ADRCs [225,226], and there are substantial differences between cultured stem cells derived from various human tissues [227]. The latter argument also applies to the 56 studies included in the 19 assessed meta-analyses, which further diminishes the value of these meta-analyses as an assessment of the management of pkOA with stem cells.
Furthermore, a meta-analysis requires that, in all included studies, the same type of data is reported (i.e., same assessment scores; same or very similar intervals between treatment and follow-up; and mean, standard deviation, and number of patients in each group). As shown in Table 11, this was not achieved for the clinical studies on the management of pkOA with autologous ADRCs, autologous ADSCs, and autologous BM-MSCs listed in Table 10.

4. Discussion

Concerning the first quality criterion outlined in Table 5, it should be mentioned that a meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Hence, calculating the overall effects based on a single study should not be considered a meta-analysis. However, calculating the overall effects based on a single study is exactly what was performed in 5 of the 19 assessed meta-analyses [206,209,214,215,216] and 16 of the 157 (10.2%) sub-analyses listed in Tables S4–S15.
With respect to the second and third quality criteria outlined in Table 5, it appears obvious that, in meta-analyses of studies in which the management of pkOA with stem cells was investigated, only studies focusing on the management of pkOA and applying stem cells should be included. However, this was not always the case in the 19 assessed meta-analyses. The pathomechanisms of focal chondral, osteochondral, or meniscal chondral lesions [156,157,161], as well as of injuries that require partial medial meniscectomy [86], are not the same as the pathomechanisms of pkOA. This will likely impact on treatment outcomes when applying stem cells. Furthermore, despite the fact that stem cells can be isolated from amniotic fluid [228], in our opinion, the injection of allogeneic amniotic fluid itself [219] should not be considered a stem cell treatment, as it does not contain, by definition, stems cells, though it may contain products of secretion by stem cells.
Concerning the fourth quality criterion outlined in Table 5, non-randomized clinical trials and studies in which the contralateral knee was used as an internal control may differ from RCTs in terms of selection bias (as a result of systematic differences between the baseline characteristics of the groups that are compared [229]), performance bias (as a result of systematic differences between groups in the care that is provided or in exposure to factors other than the interventions of interest [230]), and attrition bias (as a result of systematic differences between groups in withdrawals from a study [229]). Accordingly, non-randomized clinical trials and studies in which the contralateral knee was used as an internal control should not be combined with RCTs in meta-analyses. However, this quality criterion was not fulfilled in 24 of the 157 (15.3%) sub-analyses performed in the twelve assessed meta-analyses (Category 1 in Table 4).
With respect to the fifth quality criterion outlined in Table 5, it is crucial to bear in mind that studies in which the management of pkOA with stem cells was compared to placebo treatment (or studies in which the management of pkOA with stem cells plus a concomitant therapy was compared to the concomitant therapy alone, respectively) must not be combined with studies in which the management of pkOA with stem cells (with or without concomitant therapy) was compared to a different treatment. However, this quality criterion was not fulfilled in 102 of the 157 (65.0%) sub-analyses performed in the twelve assessed meta-analyses. Specifically, in 86 of the 157 (54.8%) sub-analyses performed in the twelve assessed meta-analyses, studies in which the management of pkOA with stem cells was compared with placebo treatment (or studies in which the management of pkOA with stem cells plus concomitant therapy was compared with the concomitant therapy alone, respectively) were combined with studies in which the management of pkOA with stem cells was compared with the injection of HA. However, this approach disregards the documented, positive effects of injection of HA as the management of pkOA [11] and may thus substantially underestimate the positive effects of treating pkOA with stem cells in meta-analyses. Furthermore, in 9 of the 157 (5.7%) sub-analyses performed in the twelve assessed meta-analyses, only studies in which the management of pkOA with stem cells was compared with the management of pkOA with the injection of HA were included. Due to the documented, positive effects of the injection of HA injection as the management of pkOA [11], these sub-analyses may reach a different conclusion than sub-analyses in which only studies in which the management of pkOA with stem cells was compared with placebo treatment were included (or studies in which the management of pkOA with stem cells plus concomitant therapy was compared with the concomitant therapy alone, respectively).
Concerning the sixth quality criterion outlined in Table 5, it is of note that, in contrast to autologous cells, the application of allogeneic cells bears the risk of a HLA mismatch; compromised clinical outcomes after application of allogeneic cells were repeatedly reported in the literature [231,232,233]. In a position statement recently published by representatives of the U.S. Food and Drug Administration (FDA) in The New England Journal of Medicine [234], it was stated that autologous stem cells may typically raise fewer safety concerns than allogeneic stem cells. Consequently, studies using autologous stem cells should not be combined with studies using allogeneic stem cells in meta-analyses. However, this quality criterion was not fulfilled in 93 of the 157 (59.2%) sub-analyses performed in the twelve assessed meta-analyses.
With respect to the seventh quality criterion outlined in Table 5, ADSCs and BM-MSCs are expanded in culture before application, whereas ADRCs and BMAC are not. As a consequence, the percentage of certain cell types in ADSCs fundamentally differs from the percentage of the same cell types in ADRCs [226], and the percentage of certain cell types in BM-MSCs fundamentally differs from the percentage of the same cell types in BMAC [235]. Hence, in meta-analyses of studies in which pkOA was treated with stem cells studies in which cultured cells were applied should not be combined with studies in which uncultured cells were applied. However, this quality criterion was not fulfilled in 24 of the 157 (15.3%) sub-analyses performed in the twelve assessed meta-analyses.
Concerning the eighth quality criterion outlined in Table 5, it should be realized that each study has its own inclusion and exclusion criteria which may vary among studies. Furthermore, there are many different ways to prepare a certain type of stem cell (e.g., approximately 40 different approaches to isolate ADRCs from adipose tissue are reported in the literature, with substantial inter-individual variations in the final cell suspensions [225]). Accordingly, considering the same study more than once in a meta-analysis can introduce bias. For example, Maheshwer et al. [215] performed a sub-analysis of changes in mean cartilage volume after treatment of pkOA with adipose-derived stem cells in their meta-analysis (Table S14). Four out of the five datasets used in this sub-analysis were taken from the same clinical study by Lu et al. [23]. Actually, these four datasets represented the same patients in four different ways (femoral cartilage volume of the left leg, femoral cartilage volume of the right leg, total cartilage volume of the left leg, and total cartilage volume of the right leg) (Figure 5 in the meta-analysis by Mashewer et al. [215]). Accordingly, this sub-analysis in the meta-analysis by Maheshwer et al. [215] could have come to a different conclusion if the study by Lu et al. [23] were considered only once in this sub-analysis. The eighth quality criterion outlined in Table 5 was not fulfilled in 57 of the 157 (36.3%) sub-analyses performed in the twelve assessed meta-analyses.
We cannot offer any explanation as to why the 19 assessed meta-analyses did not adhere to the quality criteria summarized in Table 5. As outlined in detail above, these quality criteria reflect general considerations about meta-analyses and the comparability of different types of stem cells with regard to their safety and regenerative potential.
For the sake of completeness, it should be mentioned that, recently, the application of stem cells isolated from infrapatellar fat pads was proposed for the management of pkOA, mostly due to their ability for differentiation into chondrocytes and constitutive immunomodulatory properties (reviewed in [236,237]). On the other hand, some authors have argued (based on in vitro investigations of stem cells isolated from the infrapatellar fat pad of patients suffering from pkOA) that these cells may not be effective to counteract NAD+-mediated inflammation, which is an important signature of osteoarthritis [238]. Another potential disadvantage of the application of stem cells isolated from infrapatellar fat pads is the need for surgery to harvest parts of the infrapatellar fat pad, which may add additional safety issues to the management of pkOA (potential contamination of the knee joint). Hence, clinical studies are necessary to demonstrate the potential advantages of stem cells isolated from human infrapatellar fat pads over other types of stem cells in the management of pkOA. In this regard, a very recent, first-in-human case series on 12 patients without a control group indicated that the management of pkOA with these cells is safe and effective [195]. However, the data presented in this study [195] do not indicate that stem cells isolated from human infrapatellar fat pads will outperform other types of stem cells in the management of pkOA. This can be seen from data provided in Table S2 in Supplementary Material of [195]. In this table, the authors provided individual Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores of the 12 patients at baseline and the improvement 24 weeks post-treatment. In order to compare their results with the results of other clinical studies mentioned in Table S2 in [195], the authors applied linear regression analysis (data from baseline and 24 weeks post-treatment) in order to calculate slopes of improvement and found that their approach resulted in the steepest regression line (and, thus, best outcome) compared to the other studies listed in Table S2 of [195]. However, it should be taken into account that, among those studies listed in Table S2 in [195], their own study reported the lowest mean WOMAC score at baseline (28.6) (higher WOMAC scores indicate worse pain, stiffness, and functional limitations). The other studies listed in Table S2 in [195] reported mean WOMAC scores at baselines of, respectively, 31.2 [29], 38.8 [38], and 69.0 [37]. Accordingly, one cannot exclude that the finding of the steepest regression line between the WOMAC scores at baseline and the WOMAC scores at 24 weeks post-treatment in [195] compared with the other studies listed in Table S2 in [195] was influenced by the fact that the patients in [195] had the best starting conditions for experiencing treatment success. Furthermore, the authors of [195] could have compared their data with results reported in [19] (not cited in [238]). In [19], a decrease in the mean WOMAC score from 50 at baseline to 10 at 24 weeks post treatment was reported, resulting in a slope of improvement that outperformed the slope of improvement reported in [195]. The key difference between [19] and [195] is the fact that patients were treated with uncultured ADRCs in [19] but with cultured stem cells isolated from infrapatellar fat pads in [195]. The specific advantages of uncultured ADRCs over cultured stem cells for regeneration in musculoskeletal disorders are outlined in detail in [196]. In summary, the current literature does not indicate any specific advantages of stem cells isolated from human infrapatellar fat pads over other types of stem cells in the management of pkOA.
This review had two limitations. First, only PubMed, Web of Science, and the Cochrane Library were searched. However, considering the sophisticated search strategies described in the 19 assessed meta-analyses and inclusion of all studies that were included in the 19 assessed meta-analyses also in the present investigation minimized the risk to overlook any relevant clinical study on the management of pkOA with stem cells. Second, no meta-analyses published before 2020 were assessed. However, this does not devalue our finding that the 19 meta-analyses published from January 2020 to July 2021 were not scientifically sound.

5. Conclusions

The inconsistent conclusions of the 19 assessed meta-analyses regarding the efficacy and safety of treating pkOA with stem cells were most probably based on substantial inter-individual differences in literature search strategies among different authors, misconceptions about meta-analyses themselves, and misconceptions about the comparability of different types of stem cells with regard to their safety and regenerative potential. None of the 19 assessed meta-analyses should be considered as being able to provide a scientifically definitive assessment of the efficacy of treating pkOA with stem cells. Accordingly, clinicians should be cautious of the 19 assessed meta-analyses of clinical studies on the management of pkOA with stem cells and the conclusions drawn therein and strive to participate in FDA and/or EMA approved trials that have been reviewed to provide clinically and statistically valid efficacy.
Furthermore, at this time, it appears impossible to perform a scientifically sound meta-analysis of such a heterogenous set of studies which investigated the management of pkOA with stem cells. There are strong indications that the management of pkOA with stem cells is safe and effective (e.g., all RCTs in Category I in Table S1 reported the superiority of the management of pkOA over treatment with a placebo). However, apparently it is still too early for scientifically sound meta-analyses on this topic.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cells11060965/s1: Table S1: Details of studies that were identified during an evidence-based, systematic review of the literature according to the PRISMA guidelines [198] performed on 7 August 2021 in order to examine studies on treatment of primary knee osteoarthritis with stem cells. Table S2: Conclusions of 19 meta-analyses (published between January 2020 and July 2021) of studies, in which treatment of primary knee osteoarthritis with different types of stem cells were investigated. Table S3: Details of the studies included in the meta-analyses summarized in Table S1, in which the treatment of primary knee osteoarthritis (pkOA) with different types of stem cells was investigated. Table S4: Details of the sub-analyses performed in a meta-analysis by Jiang et al. [199]. Table S5: Details of the sub-analyses performed in a meta-analysis by Qu and Sun [200]. Table S6: Details of the sub-analyses performed in a meta-analysis by Ma et al. [201]. Table S7: Details of the sub-analyses performed in a meta-analysis by Huang et al. [203]. Table S8: Details of the sub-analyses performed in a meta-analysis by Wei et al. [205]. Table S9: Details of the sub-analyses performed in a meta-analysis by Wang et al. [206]. Table S10: Details of the sub-analyses performed in a meta-analysis by Jeyaraman et al. [208]. Table S11: Details of the sub-analyses performed in a meta-analysis by Han et al. [209]. Table S12: Details of the sub-analyses performed in a meta-analysis by Kim et al. [213]. Table S13: Details of the sub-analyses performed in a meta-analysis by Ding et al. [214]. Table S14: Details of the sub-analyses performed in a meta-analysis by Maheshwer et al. [215]. Table S15: Details of the sub-analyses performed in a meta-analysis by Dai et al. [216].

Author Contributions

Conceptualization, C.S. and E.U.A.; methodology, C.S.; validation, C.A. and D.A.P.; formal analysis, C.S. and C.A.; investigation, C.S. and C.A.; resources, C.S.; data curation, C.S.; writing–original draft preparation, C.S.; writing–review and editing, C.S., C.A., D.A.P., J.P.F., N.M. and E.U.A.; visualization, C.S.; supervision, E.U.A.; project administration, C.S. and E.U.A.; funding acquisition, not applicable. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All relevant data are reported in the manuscript and Tables S1–S15.

Conflicts of Interest

C.S. is the Advisory Medical Director of InGeneron, Inc. (Houston, TX, USA). C.A. is the Director of Medical and Scientific Affairs of InGeneron. E.U.A. is the Executive Chair of InGeneron. InGeneron had no role in study design, data collection and analysis, or interpretation of the data, and no role in the decision to publish and write this manuscript. No other potential conflicts of interest relevant to this article were reported.

References

  1. Felson, D.T. Osteoarthritis of the Knee. N. Engl. J. Med. 2006, 354, 841–848. [Google Scholar] [CrossRef] [PubMed]
  2. Loeser, R.F.; Goldring, S.R.; Scanzello, C.R.; Goldring, M.B. Osteoarthritis: A disease of the joint as an organ. Arthritis Rheum. 2012, 64, 1697–1707. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Fransen, M.; Agaliotis, M.; Bridgett, L.; Mackey, M.G. Hip and knee pain: Role of occupational factors. Best Pract. Res. Clin. Rheumatol. 2011, 25, 81–101. [Google Scholar] [CrossRef] [PubMed]
  4. Salaffi, F.; Ciapetti, A.; Carotti, M. The sources of pain in osteoarthritis: A pathophysiological review. Reumatismo 2014, 66, 57–71. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Di Nicola, V. Degenerative osteoarthritis a reversible chronic disease. Regen. Ther. 2020, 15, 149–160. [Google Scholar] [CrossRef] [PubMed]
  6. Lluch Girbés, E.; Nijs, J.; Torres-Cueco, R.; López Cubas, C. Pain treatment for patients with osteoarthritis and central sensitization. Phys. Ther. 2013, 93, 842–851. [Google Scholar] [CrossRef] [Green Version]
  7. Carr, A.J.; Robertsson, O.; Graves, S.; Price, A.J.; Arden, N.K.; Judge, A.; Beard, D.J. Knee replacement. Lancet 2012, 379, 1331–1340. [Google Scholar] [CrossRef]
  8. Jüni, P.; Hari, R.; Rutjes, A.W.; Fischer, R.; Silletta, M.G.; Reichenbach, S.; da Costa, B.R. Intra-articular corticosteroid for knee osteoarthritis. Cochrane Database Syst. Rev. 2015, 10, CD005328. [Google Scholar] [CrossRef] [Green Version]
  9. Meheux, C.J.; McCulloch, P.C.; Lintner, D.M.; Varner, K.E.; Harris, J.D. Efficacy of intra-articular platelet-rich plasma injections in knee osteoarthritis: A systematic review. Arthroscopy 2016, 32, 495–505. [Google Scholar] [CrossRef]
  10. Bannuru, R.R.; Osani, M.C.; Vaysbrot, E.E.; Arden, N.K.; Bennell, K.; Bierma-Zeinstra, S.M.A.; Kraus, V.B.; Lohmander, L.S.; Abbott, J.H.; Bhandari, M.; et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthr. Cartil. 2019, 27, 1578–1589. [Google Scholar] [CrossRef] [Green Version]
  11. He, W.; Kuang, M.; Zhao, J.; Sun, L.; Lu, B.; Wang, Y.; Ma, J.; Ma, X. Efficacy and safety of intraarticular hyaluronic acid and corticosteroid for knee osteoarthritis: A meta-analysis. Int. J. Surg. 2017, 39, 95–103. [Google Scholar] [CrossRef] [PubMed]
  12. Cherian, J.J.; Parvizi, J.; Bramlet, D.; Lee, K.H.; Romness, D.W.; Mont, M.A. Preliminary results of a phase ii randomized study to determine the efficacy and safety of genetically engineered allogeneic human chondrocytes expressing tgf-β1 in patients with grade 3 chronic degenerative joint disease of the knee. Osteoarthr. Cartil. 2015, 23, 2109–2118. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Gupta, P.K.; Chullikana, A.; Rengasamy, M.; Shetty, N.; Pandey, V.; Agarwal, V.; Wagh, S.Y.; Vellotare, P.K.; Damodaran, D.; Viswanathan, P.; et al. Efficacy and safety of adult human bone-marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®): Preclinical and clinical trial in osteoarthritis of the knee joint. Arthritis Res. Ther. 2016, 18, 301. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Emadedin, M.; Labibzadeh, N.; Liastani, M.G.; Karimi, A.; Jaroughi, N.; Bolurieh, T.; Hosseini, S.-E.; Baharvand, H.; Aghdami, N. Intra-articular implantation of autologous bone marrow–derived mesenchymal stromal cells to treat knee osteoarthritis: A randomized, triple-blind, placebo-controlled phase 1/2 clinical trial. Cytotherapy 2018, 20, 1238–1246. [Google Scholar] [CrossRef] [PubMed]
  15. Kim, M.-K.; Ha, C.-W.; In, Y.; Cho, S.-D.; Choi, E.-S.; Ha, J.-K.; Lee, J.-H.; Yoo, J.-D.; Bin, S.-I.; Choi, C.-H.; et al. A Multicenter, double-blind, Phase III clinical trial to evaluate the efficacy and safety of a cell and gene therapy in knee osteoarthritis patients. Hum. Gene Ther. Clin. Dev. 2018, 29, 48–59. [Google Scholar] [CrossRef]
  16. Kuah, D.; Sivell, S.; Longworth, T.; James, K.; Guermazi, A.; Cicuttini, F.; Wang, Y.; Craig, S.; Comin, G.; Robinson, D.; et al. Safety, tolerability and efficacy of intra-articular progenza in knee osteoarthritis: A randomized double-blind placebo-controlled single ascending dose study. J. Transl. Med. 2018, 16, 49. [Google Scholar] [CrossRef] [Green Version]
  17. Khalifeh Soltani, S.; Forogh, B.; Ahmadbeigi, N.; Hadizadeh Kharazi, H.; Fallahzadeh, K.; Kashani, L.; Karami, M.; Kheyrollah, Y.; Vasei, M. Safety and efficacy of allogenic placental mesenchymal stem cells for treating knee osteoarthritis: A pilot study. Cytotherapy 2019, 21, 54–63. [Google Scholar] [CrossRef]
  18. Lee, W.-S.; Kim, H.J.; Kim, K.-I.; Kim, G.B.; Jin, W. Intra-articular injection of autologous adipose tissue-derived mesenchymal stem cells for the treatment of knee osteoarthritis: A Phase IIb, randomized, placebo-controlled clinical trial. Stem Cells Transl. Med. 2019, 8, 504–511. [Google Scholar] [CrossRef] [Green Version]
  19. Garza, J.R.; Campbell, R.E.; Tjoumakaris, F.P.; Freedman, K.B.; Miller, L.S.; Santa Maria, D.; Tucker, B.S. Clinical efficacy of intra-articular mesenchymal stromal cells for the treatment of knee osteoarthritis: A double-blinded prospective randomized controlled clinical trial. Am. J. Sports Med. 2020, 48, 588–598. [Google Scholar] [CrossRef]
  20. Vega, A.; Martín-Ferrero, M.A.; Del Canto, F.; Alberca, M.; García, V.; Munar, A.; Orozco, L.; Soler, R.; Fuertes, J.J.; Huguet, M.; et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: A randomized controlled trial. Transplantation 2015, 99, 1681–1690. [Google Scholar] [CrossRef]
  21. Wang, Y.; Jin, W.; Liu, H.; Cui, Y.; Mao, Q.; Fei, Z.; Xiang, C. Curative effect of human umbilical cord mesenchymal stem cells by intra-articular injection for degenerative knee osteoarthritis. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2016, 30, 1472–1477. (In Chinese) [Google Scholar] [PubMed]
  22. Goncars, V.; Jakobsons, E.; Blums, K.; Briede, I.; Patetko, L.; Erglis, K.; Erglis, M.; Kalnberzs, K.; Muiznieks, I.; Erglis, A. The comparison of knee osteoarthritis treatment with single-dose bone-marrow-derived mononuclear cells vs. hyaluronic acid injections. Medicina 2017, 53, 101–108. [Google Scholar] [CrossRef] [PubMed]
  23. Lu, L.; Dai, C.; Zhang, Z.; Du, H.; Li, S.; Ye, P.; Fu, Q.; Zhang, L.; Wu, X.; Dong, Y.; et al. Treatment of knee osteoarthritis with intra-articular injection of autologous adipose-derived mesenchymal progenitor cells: A prospective, randomized, double-blind, active-controlled, Phase IIb clinical trial. Stem Cell Res. Ther. 2019, 10, 143. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Matas, J.; Orrego, M.; Amenabar, D.; Infante, C.; Tapia-Limonchi, R.; Cadiz, M.I.; Alcayaga-Miranda, F.; González, P.L.; Muse, E.; Khoury, M.; et al. Umbilical cord-derived mesenchymal stromal cells (MSCs) for knee osteoarthritis: Repeated MSC dosing is superior to a single MSC dose and to hyaluronic acid in a controlled randomized Phase I/II trial. Stem Cells Transl. Med. 2019, 8, 215–224. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Anz, A.W.; Hubbard, R.; Rendos, N.K.; Everts, P.A.; Andrews, J.R.; Hackel, J.G. Bone marrow aspirate concentrate is equivalent to platelet-rich plasma for the treatment of knee osteoarthritis at 1 year: A prospective, randomized trial. Orthop. J. Sports Med. 2020, 8, 232596711990095. [Google Scholar] [CrossRef] [Green Version]
  26. Dallo, I.; Szwedowski, D.; Mobasheri, A.; Irlandini, E.; Gobbi, A. A prospective study comparing leukocyte-poor platelet-rich plasma combined with hyaluronic acid and autologous microfragmented adipose tissue in patients with early knee osteoarthritis. Stem Cells Dev. 2021, 30, 651–659. [Google Scholar] [CrossRef]
  27. Kim, Y.S.; Suh, D.S.; Tak, D.H.; Chung, P.K.; Kwon, Y.B.; Kim, T.Y.; Koh, Y.G. Comparative matched-pair cohort analysis of the short-term clinical outcomes of mesenchymal stem cells versus hyaluronic acid treatments through intra-articular injections for knee osteoarthritis. J. Exp. Ortop. 2020, 7, 90. [Google Scholar] [CrossRef]
  28. Garay-Mendoza, D.; Villarreal-Martínez, L.; Garza-Bedolla, A.; Pérez-Garza, D.M.; Acosta-Olivo, C.; Vilchez-Cavazos, F.; Diaz-Hutchinson, C.; Gómez-Almaguer, D.; Jaime-Pérez, J.C.; Mancías-Guerra, C. The effect of intra-articular injection of autologous bone marrow stem cells on pain and knee function in patients with osteoarthritis. Int. J. Rheum. Dis. 2018, 21, 140–147. [Google Scholar] [CrossRef] [Green Version]
  29. Song, Y.; Du, H.; Dai, C.; Zhang, L.; Li, S.; Hunter, D.J.; Lu, L.; Bao, C. Human adipose-derived mesenchymal stem cells for osteoarthritis: A pilot study with long-term follow-up and repeated injections. Regen. Med. 2018, 13, 295–307. [Google Scholar] [CrossRef]
  30. Freitag, J.; Bates, D.; Wickham, J.; Shah, K.; Huguenin, L.; Tenen, A.; Paterson, K.; Boyd, R. Adipose-derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis: A randomized controlled trial. Regen. Med. 2019, 14, 213–230. [Google Scholar] [CrossRef] [Green Version]
  31. Zhao, X.; Ruan, J.; Tang, H.; Li, J.; Shi, Y.; Li, M.; Li, S.; Xu, C.; Lu, Q.; Dai, C. Multi-compositional MRI evaluation of repair cartilage in knee osteoarthritis with treatment of allogeneic human adipose-derived mesenchymal progenitor cells. Stem Cell Res. Ther. 2019, 10, 308. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Bastos, R.; Mathias, M.; Andrade, R.; Amaral, R.J.F.C.; Schott, V.; Balduino, A.; Bastos, R.; Miguel Oliveira, J.; Reis, R.L.; Rodeo, S.; et al. Intra-articular injection of culture-expanded mesenchymal stem cells with or without addition of platelet-rich plasma is effective in decreasing pain and symptoms in knee osteoarthritis: A controlled, double-blind clinical trial. Knee Surg. Sports Traumatol. Arthrosc. 2020, 28, 1989–1999. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Lu, L.; Dai, C.; Du, H.; Li, S.; Ye, P.; Zhang, L.; Wang, X.; Song, Y.; Togashi, R.; Vangsness, C.T.; et al. Intra-articular injections of allogeneic human adipose-derived mesenchymal progenitor cells in patients with symptomatic bilateral knee osteoarthritis: A Phase I pilot study. Regen. Med. 2020, 15, 1625–1636. [Google Scholar] [CrossRef] [PubMed]
  34. Hernigou, P.; Auregan, J.C.; Dubory, A.; Flouzat-Lachaniette, C.H.; Chevallier, N.; Rouard, H. Subchondral stem cell therapy versus contralateral total knee arthroplasty for osteoarthritis following secondary osteonecrosis of the knee. Int. Orthop. 2018, 42, 2563–2571. [Google Scholar] [CrossRef] [PubMed]
  35. Hernigou, P.; Bouthors, C.; Bastard, C.; Flouzat Lachaniette, C.H.; Rouard, H.; Dubory, A. Subchondral bone or intra-articular injection of bone marrow concentrate mesenchymal stem cells in bilateral knee osteoarthritis: What better postpone knee arthroplasty at fifteen years? A randomized study. Int. Orthop. 2021, 45, 391–399. [Google Scholar] [CrossRef]
  36. Hernigou, P.; Delambre, J.; Quiennec, S.; Poignard, A. Human bone marrow mesenchymal stem cell injection in subchondral lesions of knee osteoarthritis: A prospective randomized study versus contralateral arthroplasty at a mean fifteen year follow-up. Int. Orthop. 2021, 45, 365–373. [Google Scholar] [CrossRef]
  37. Jo, C.H.; Lee, Y.G.; Shin, W.H.; Kim, H.; Chai, J.W.; Jeong, E.C.; Kim, J.E.; Shim, H.; Shin, J.S.; Shin, I.S.; et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: A proof-of-concept clinical trial. Stem Cells 2014, 32, 1254–1266. [Google Scholar] [CrossRef]
  38. Pers, Y.-M.; Rackwitz, L.; Ferreira, R.; Pullig, O.; Delfour, C.; Barry, F.; Sensebe, L.; Casteilla, L.; Fleury, S.; Bourin, P.; et al. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: A Phase I dose-escalation trial. Stem Cells Transl. Med. 2016, 5, 847–856. [Google Scholar] [CrossRef] [Green Version]
  39. Jo, C.H.; Chai, J.W.; Jeong, E.C.; Oh, S.; Shin, J.S.; Shim, H.; Yoon, K.S. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: A 2-year follow-up study. Am. J. Sports Med. 2017, 45, 2774–2783. [Google Scholar] [CrossRef]
  40. Pers, Y.-M.; Quentin, J.; Feirreira, R.; Espinoza, F.; Abdellaoui, N.; Erkilic, N.; Cren, M.; Dufourcq-Lopez, E.; Pullig, O.; Nöth, U.; et al. Injection of adipose-derived stromal cells in the knee of patients with severe osteoarthritis has a systemic effect and promotes an anti-inflammatory phenotype of circulating immune cells. Theranostics 2018, 8, 5519–5528. [Google Scholar] [CrossRef]
  41. Chahal, J.; Gómez-Aristizábal, A.; Shestopaloff, K.; Bhatt, S.; Chaboureau, A.; Fazio, A.; Chisholm, J.; Weston, A.; Chiovitti, J.; Keating, A.; et al. Bone marrow mesenchymal stromal cell treatment in patients with osteoarthritis results in overall improvement in pain and symptoms and reduces synovial inflammation. Stem Cells Transl. Med. 2019, 8, 746–757. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Estrada, E.; Décima, J.L.; Rodríguez, M.; Di Tomaso, M.; Roberti, J. Patient-reported outcomes after platelet-rich plasma, bone marrow aspirate, and adipose-derived mesenchymal stem cell injections for symptomatic knee osteoarthritis. Clin. Med. Insights Arthritis Musculoskelet. Disord. 2020, 13, 117954412093108. [Google Scholar] [CrossRef] [PubMed]
  43. Kazemian, G.; Manafi Rasi, A.; Baroutkoub, M.; Tavakoli Darestani, R. Effect of administration of mesenchymal stem cells on cartilage recovery and knee function in patients with knee osteoarthritis. Med. Sci. 2020, 24, 1019–1026. [Google Scholar]
  44. Papalia, R.; Zampogna, B.; Russo, F.; Vasta, S.; Campi, S.; Saccone, L.; Di Giacomo, G.; Vadalà, G.; Denaro, V. Adipose-derived stromal vascular fraction processed with different systems for the treatment of knee osteoarthritis: A pilot study on cell proliferation and clinical results. J. Biol. Regul. Homeost. Agents 2020, 34, 113–119. [Google Scholar] [PubMed]
  45. Bistolfi, A.; Roato, I.; Fornelli, G.; Sabatini, L.; Massè, A.; Ferracini, R. Treatment of knee osteoarthritis by intra-articular injection of concentrated autologous adipose tissue: A twenty four month follow-up study. Int. Orthop. 2021, 45, 627–633. [Google Scholar] [CrossRef] [PubMed]
  46. Mautner, K.; Bowers, R.; Easley, K.; Fausel, Z.; Robinson, R. Functional outcomes following microfragmented adipose tissue versus bone marrow aspirate concentrate injections for symptomatic knee osteoarthritis. Stem Cells Transl. Med. 2019, 8, 1149–1156. [Google Scholar] [CrossRef] [Green Version]
  47. Yokota, N.; Hattori, M.; Ohtsuru, T.; Otsuji, M.; Lyman, S.; Shimomura, K.; Nakamura, N. Comparative clinical outcomes after intra-articular injection with adipose-derived cultured stem cells or noncultured stromal vascular fraction for the treatment of knee osteoarthritis. Am. J. Sports Med. 2019, 47, 2577–2583. [Google Scholar] [CrossRef]
  48. Li, J.; Shao, Q.; Zhu, X.; Sun, G. Efficacy of autologous bone marrow mesenchymal stem cells in the treatment of knee osteoarthritis and their effects on the expression of serum TNF-α and IL-6. J. Musculoskelet. Neuronal. Interact. 2020, 20, 128–135. [Google Scholar] [PubMed]
  49. Simunec, D.; Salari, H.; Meyer, J. Treatment of Grade 3 and 4 osteoarthritis with intraoperatively separated adipose tissue-derived stromal vascular fraction: A comparative case series. Cells 2020, 9, 2096. [Google Scholar] [CrossRef]
  50. Varma, H.S.; Dadarya, B.; Vidyarthi, A. The new avenues in the management of osteo-arthritis of knee—Stem cells. J. Indian Med. Assoc. 2010, 108, 583–585. [Google Scholar]
  51. Wong, K.L.; Lee, K.B.L.; Tai, B.C.; Law, P.; Lee, E.H.; Hui, J.H.P. Injectable cultured bone marrow–derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: A prospective, randomized controlled clinical trial with 2 years’ follow-up. Arthroscopy 2013, 29, 2020–2028. [Google Scholar] [CrossRef] [PubMed]
  52. Koh, Y.-G.; Kwon, O.-R.; Kim, Y.-S.; Choi, Y.-J. Comparative outcomes of open-wedge high tibial osteotomy with platelet-rich plasma alone or in combination with mesenchymal stem cell treatment: A prospective study. Arthroscopy 2014, 30, 1453–1460. [Google Scholar] [CrossRef] [PubMed]
  53. Lamo-Espinosa, J.M.; Mora, G.; Blanco, J.F.; Granero-Moltó, F.; Nuñez-Córdoba, J.M.; Sánchez-Echenique, C.; Bondía, J.M.; Aquerreta, J.D.; Andreu, E.J.; Ornilla, E.; et al. Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: Multicenter randomized controlled clinical trial (Phase I/II). J. Transl. Med. 2016, 14, 246. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Turajane, T.; Chaveewanakorn, U.; Fongsarun, W.; Aojanepong, J.; Papadopoulos, K.I. Avoidance of total knee arthroplasty in early osteoarthritis of the knee with intra-articular implantation of autologous activated peripheral blood stem cells versus hyaluronic acid: A randomized controlled trial with differential effects of growth factor addition. Stem Cells Int. 2017, 2017, 1–10. [Google Scholar]
  55. Bastos, R.; Mathias, M.; Andrade, R.; Bastos, R.; Balduino, A.; Schott, V.; Rodeo, S.; Espregueira-Mendes, J. Intra-articular injections of expanded mesenchymal stem cells with and without addition of platelet-rich plasma are safe and effective for knee osteoarthritis. Knee Surg. Sports. Traumatol. Arthrosc. 2018, 26, 3342–3350. [Google Scholar] [CrossRef]
  56. Zhang, S.Y.; Lyu, S.J.; Ding, Q.W.; Fan, M.Q.; Tong, P.J. Intraarticular injection of autologous adipose-derived stem cells for knee osteoarthritis: A randomized controlled trial. Zhong Hua Gu Ke Za Zhi 2018, 38, 1426–1434. (In Chinese) [Google Scholar]
  57. Lamo-Espinosa, J.M.; Mora, G.; Blanco, J.F.; Granero-Moltó, F.; Núñez-Córdoba, J.M.; López-Elío, S.; Andreu, E.; Sánchez-Guijo, F.; Aquerreta, J.D.; Bondía, J.M.; 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: Long-term follow up of a multicenter randomized controlled clinical trial (Phase I/II). J. Transl. Med. 2018, 16, 213. [Google Scholar] [CrossRef] [Green Version]
  58. Peretti, G.M.; Ulivi, M.; De Girolamo, L.; Meroni, V.; Lombardo, M.D.; Mangiavini, L. Evaluation of the use of autologous micro-fragmented adipose tissue in the treatment of knee osteoarthritis: Preliminary results of a randomized controlled trial. J. Biol. Regul. Homeost. Agents 2018, 32, 193–199. [Google Scholar]
  59. Lamo-Espinosa, J.M.; Blanco, J.F.; Sánchez, M.; Moreno, V.; Granero-Moltó, F.; Sánchez-Guijo, F.; Crespo-Cullel, Í.; Mora, G.; San Vicente, D.D.; Pompei-Fernández, O.; et al. Phase II multicenter randomized controlled clinical trial on the efficacy of intra-articular injection of autologous bone marrow mesenchymal stem cells with platelet rich plasma for the treatment of knee osteoarthritis. J. Transl. Med. 2020, 18, 356. [Google Scholar] [CrossRef]
  60. Qiao, Z.; Tang, J.; Yue, B.; Wang, J.; Zhang, J.; Xuan, L.; Dai, C.; Li, S.; Li, M.; Xu, C.; et al. Human adipose-derived mesenchymal progenitor cells plus microfracture and hyaluronic acid for cartilage repair: A Phase IIa trial. Regen. Med. 2020, 15, 1193–1214. [Google Scholar] [CrossRef] [Green Version]
  61. Ruane, J.J.; Ross, A.; Zigmont, V.; McClure, D.; Gascon, G. A Single-blinded randomized controlled trial of mesenchymal stem cell therapy for the treatment of osteoarthritis of the knee with active control. J. Stem Cells Regen. Med. 2021, 17, 3–17. [Google Scholar] [PubMed]
  62. Shapiro, S.A.; Kazmerchak, S.E.; Heckman, M.G.; Zubair, A.C.; O’Connor, M.I. A Prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis. Am. J. Sports Med. 2017, 45, 82–90. [Google Scholar] [CrossRef] [PubMed]
  63. Hong, Z.; Chen, J.; Zhang, S.; Zhao, C.; Bi, M.; Chen, X.; Bi, Q. Intra-articular injection of autologous adipose-derived stromal vascular fractions for knee osteoarthritis: A double-blind randomized self-controlled trial. Int. Orthop. 2019, 43, 1123–1134. [Google Scholar] [CrossRef] [PubMed]
  64. Shapiro, S.A.; Arthurs, J.R.; Heckman, M.G.; Bestic, J.M.; Kazmerchak, S.E.; Diehl, N.N.; Zubair, A.C.; O’Connor, M.I. Quantitative T2 MRI mapping and 12-month follow-up in a randomized, blinded, placebo controlled trial of bone marrow aspiration and concentration for osteoarthritis of the knees. Cartilage 2019, 10, 432–443. [Google Scholar] [CrossRef] [PubMed]
  65. Koh, Y.-G.; Choi, Y.-J. Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis. Knee 2012, 19, 902–907. [Google Scholar] [CrossRef] [PubMed]
  66. Kim, Y.S.; Kwon, O.R.; Choi, Y.J.; Suh, D.S.; Heo, D.B.; Koh, Y.G. Comparative matched-pair analysis of the injection versus implantation of mesenchymal stem cells for knee osteoarthritis. Am. J. Sports Med. 2015, 43, 2738–2746. [Google Scholar] [CrossRef]
  67. Nguyen, P.D.; Tran, T.D.-X.; Nguyen, H.T.-N.; Vu, H.T.; Le, P.T.-B.; Phan, N.L.-C.; Vu, N.B.; Phan, N.K.; Van Pham, P. Comparative clinical observation of arthroscopic microfracture in the presence and absence of a stromal vascular fraction injection for osteoarthritis. Stem Cells Transl. Med. 2017, 6, 187–195. [Google Scholar] [CrossRef] [PubMed]
  68. Kim, Y.S.; Koh, Y.G. Comparative matched-pair analysis of open-wedge high tibial osteotomy with versus without an injection of adipose-derived mesenchymal stem cells for varus knee osteoarthritis: Clinical and second-look arthroscopic results. Am. J. Sports Med. 2018, 46, 2669–2677. [Google Scholar] [CrossRef]
  69. Tran, T.D.X.; Wu, C.-M.; Dubey, N.K.; Deng, Y.-H.; Su, C.-W.; Pham, T.T.; Thi Le, P.B.; Sestili, P.; Deng, W.-P. Time- and Kellgren–Lawrence grade-dependent changes in intra-articularly transplanted stromal vascular fraction in osteoarthritic patients. Cells 2019, 8, 308. [Google Scholar] [CrossRef] [Green Version]
  70. Ehlers, C.B.; Webb, A.R.; McCormick, B.P.; Wyand, T.J.; Sarna, N.; Povey, K.; Marano, G.; Schainker, L. Standardized platelet rich plasma injections for osteoarthritis of the knee. Cureus 2020, 12, e10900. [Google Scholar] [CrossRef]
  71. Centeno, C.; Pitts, J.; Al-Sayegh, H.; Freeman, M. Efficacy of autologous bone marrow concentrate for knee osteoarthritis with and without adipose graft. Biomed Res. Int. 2014, 2014, 1–9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Kim, Y.S.; Choi, Y.J.; Suh, D.S.; Heo, D.B.; Kim, Y.I.; Ryu, J.-S.; Koh, Y.G. Mesenchymal stem cell implantation in osteoarthritic knees: Is fibrin glue effective as a scaffold? Am. J. Sports Med. 2015, 43, 176–185. [Google Scholar] [CrossRef] [PubMed]
  73. Srinivas, P.L.; Kumar, P.P. Role of PRP and stem cell injections in osteoarthritic patients of knee joint. J. Evol. Med. Dent. Sci. 2015, 4, 9468–9474. [Google Scholar]
  74. Lee, N.-H.; Na, S.-M.; Ahn, H.-W.; Kang, J.-K.; Seon, J.-K.; Song, E.-K. Allogenic human umbilical cord blood-derived mesenchymal stem cells are more effective than bone marrow aspiration concentrate for cartilage regeneration after high tibial osteotomy in medial unicompartmental osteoarthritis of knee. Arthroscopy 2021, 37, 2521–2530. [Google Scholar] [CrossRef] [PubMed]
  75. Centeno, C.; Cartier, C.; Stemper, I.; Dodson, E.; Freeman, M.; Azuike, U.; Williams, C.; Hyzy, M.; Silva, O.; Steinmetz, N. The treatment of bone marrow lesions associated with advanced knee osteoarthritis: Comparing intraosseous and intraarticular injections with bone marrow concentrate and platelet products. Pain Physician 2021, 24, E279–E288. [Google Scholar] [PubMed]
  76. Magnanelli, S.; Screpis, D.; Di Benedetto, P.; Natali, S.; Causero, A.; Zorzi, C. Open-wedge high tibial osteotomy associated with lipogems® intra-articular injection for the treatment of varus knee osteoarthritis—Retrospective study. Acta Bio. Med. Atenei Parm. 2020, 91, e2020022. [Google Scholar]
  77. Davatchi, F.; Abdollahi, B.S.; Mohyeddin, M.; Shahram, F.; Nikbin, B. Mesenchymal stem cell therapy for knee osteoarthritis. preliminary report of four patients: Mesenchymal stem cell therapy for knee osteoarthritis. Int. J. Rheum. Dis. 2011, 14, 211–215. [Google Scholar] [CrossRef] [PubMed]
  78. Pak, J. Regeneration of human bones in hip osteonecrosis and human cartilage in knee osteoarthritis with autologous adipose-tissue-derived stem cells: A case series. J. Med. Case Rep. 2011, 5, 296. [Google Scholar] [CrossRef] [Green Version]
  79. Emadedin, M.; Aghdami, N.; Taghiyar, L.; Fazeli, R.; Moghadasali, R.; Jahangir, S.; Farjad, R.; Baghaban Eslaminejad, M. Intra-articular injection of autologous mesenchymal stem cells in six patients with knee osteoarthritis. Arch. Iran. Med. 2012, 15, 422–428. [Google Scholar]
  80. Hauser, R.A.; Orlofsky, A. Regenerative injection therapy with whole bone marrow aspirate for degenerative joint disease: A case series. Clin Med. Insights Arthritis Musculoskelet. Disord. 2013, 6, 65–72. [Google Scholar] [CrossRef]
  81. Koh, Y.-G.; Jo, S.-B.; Kwon, O.-R.; Suh, D.-S.; Lee, S.-W.; Park, S.-H.; Choi, Y.-J. Mesenchymal stem cell injections improve symptoms of knee osteoarthritis. Arthroscopy 2013, 29, 748–755. [Google Scholar] [CrossRef] [PubMed]
  82. Orozco, L.; Munar, A.; Soler, R.; Alberca, M.; Soler, F.; Huguet, M.; Sentís, J.; Sánchez, A.; García-Sancho, J. Treatment of knee osteoarthritis with autologous mesenchymal stem cells: A pilot study. Transplantation 2013, 95, 1535–1541. [Google Scholar] [CrossRef] [PubMed]
  83. Turajane, T.; Chaweewannakorn, U.; Larbpaiboonpong, V.; Aojanepong, J.; Thitiset, T.; Honsawek, S.; Fongsarun, J.; Papadopoulos, K.I. Combination of intra-articular autologous activated peripheral blood stem cells with growth factor addition/preservation and hyaluronic acid in conjunction with arthroscopic microdrilling mesenchymal cell stimulation improves quality of life and regenerates articular cartilage in early osteoarthritic knee disease. J. Med. Assoc. Thail. 2013, 96, 580–588. [Google Scholar]
  84. Ahmad, K.A.; Ibrahim, Y.A.; Saber, N.Z.; Darwish, B.A. MR cartilage imaging in assessment of the regenerative power of autologous peripheral blood stem cell injection in knee osteoarthritis. Egypt. J. Radiol. Nucl. Med. 2014, 45, 787–794. [Google Scholar] [CrossRef] [Green Version]
  85. Van Pham, P.; Bui, K.H.-T.; Duong, T.D.; Nguyen, N.T.; Nguyen, T.D.; Le, V.T.; Mai, V.T.; Phan, N.L.-C.; Le, D.M.; Ngoc, N.K. Symptomatic knee osteoarthritis treatment using autologous adipose derived stem cells and platelet-rich plasma: A clinical study. Biomed. Res. Ther. 2014, 1, 2–8. [Google Scholar] [CrossRef]
  86. Koh, Y.G.; Choi, Y.J.; Kwon, O.R.; Kim, Y.S. Second-look arthroscopic evaluation of cartilage lesions after mesenchymal stem cell implantation in osteoarthritic knees. Am. J. Sports Med. 2014, 42, 1628–1637. [Google Scholar] [CrossRef]
  87. Orozco, L.; Munar, A.; Soler, R.; Alberca, M.; Soler, F.; Huguet, M.; Sentís, J.; Sánchez, A.; García-Sancho, J. Treatment of knee osteoarthritis with autologous mesenchymal stem cells: Two-year follow-up results. Transplantation 2014, 97, e66–e68. [Google Scholar] [CrossRef]
  88. 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. BMC Musculoskelet. Disord. 2015, 16, 258. [Google Scholar] [CrossRef] [Green Version]
  89. Emadedin, M.; Ghorbani Liastani, M.; Fazeli, R.; Mohseni, F.; Moghadasali, R.; Mardpour, S.; Hosseini, S.E.; Niknejadi, M.; Moeininia, F.; Aghahossein Fanni, A.; et al. Long-term follow-up of intra-articular injection of autologous mesenchymal stem cells in patients with knee, ankle, or hip osteoarthritis. Arch. Iran. Med. 2015, 18, 336–344. [Google Scholar]
  90. Gibbs, N.; Diamond, R.; Sekyere, E.; Thomas, W. Management of knee osteoarthritis by combined stromal vascular fraction cell therapy, platelet-rich plasma, and musculoskeletal exercises: A case series. J. Pain Res. 2015, 8, 799–806. [Google Scholar] [CrossRef] [Green Version]
  91. Kim, Y.S.; Choi, Y.J.; Koh, Y.G. Mesenchymal stem cell implantation in knee osteoarthritis: An assessment of the factors influencing clinical outcomes. Am. J. Sports Med. 2015, 43, 2293–2301. [Google Scholar] [CrossRef] [PubMed]
  92. Koh, Y.-G.; Choi, Y.-J.; Kwon, S.-K.; Kim, Y.-S.; Yeo, J.-E. Clinical results and second-look arthroscopic findings after treatment with adipose-derived stem cells for knee osteoarthritis. Knee Surg. Sports Traumatol. Arthrosc. 2015, 23, 1308–1316. [Google Scholar] [CrossRef] [PubMed]
  93. Davatchi, F.; Sadeghi Abdollahi, B.; Mohyeddin, M.; Nikbin, B. Mesenchymal stem cell therapy for knee osteoarthritis: 5 years follow-up of three patients. Int. J. Rheum. Dis. 2016, 19, 219–225. [Google Scholar] [CrossRef] [PubMed]
  94. Fodor, P.B.; Paulseth, S.G. Adipose derived stromal cell (ADSC) injections for pain management of osteoarthritis in the human knee joint. Aesthet. Surg. J. 2016, 36, 229–236. [Google Scholar] [CrossRef] [Green Version]
  95. Kim, Y.S.; Choi, Y.J.; Lee, S.W.; Kwon, O.R.; Suh, D.S.; Heo, D.B.; Koh, Y.G. Assessment of clinical and mri outcomes after mesenchymal stem cell implantation in patients with knee osteoarthritis: A prospective study. Osteoarthr. Cartil. 2016, 24, 237–245. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. 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. Biores. Open Access 2016, 5, 192–200. [Google Scholar] [CrossRef]
  97. Sampson, S.; Smith, J.; Vincent, H.; Aufiero, D.; Zall, M.; Botto-van-Bemden, A. Intra-articular bone marrow concentrate injection protocol: Short-term efficacy in osteoarthritis. Regen. Med. 2016, 11, 511–520. [Google Scholar] [CrossRef] [Green Version]
  98. Soler, R.; Orozco, L.; Munar, A.; Huguet, M.; López, R.; Vives, J.; Coll, R.; Codinach, M.; Garcia-Lopez, J. Final Results of a Phase I–II trial using ex vivo expanded autologous mesenchymal stromal cells for the treatment of osteoarthritis of the knee confirming safety and suggesting cartilage regeneration. Knee 2016, 23, 647–654. [Google Scholar] [CrossRef]
  99. Al-Najar, M.; Khalil, H.; Al-Ajlouni, J.; Al-Antary, E.; Hamdan, M.; Rahmeh, R.; Alhattab, D.; Samara, O.; Yasin, M.; Abdullah, A.A.; et al. Intra-articular injection of expanded autologous bone marrow mesenchymal cells in moderate and severe knee osteoarthritis is safe: A Phase I/II study. J. Orthop. Surg. Res. 2017, 12, 190. [Google Scholar] [CrossRef]
  100. Hudetz, D.; Borić, I.; Rod, E.; Jeleč, Ž.; Radić, A.; Vrdoljak, T.; Skelin, A.; Lauc, G.; Trbojević-Akmačić, I.; Plečko, M.; et al. The effect of intra-articular injection of autologous microfragmented fat tissue on proteoglycan synthesis in patients with knee osteoarthritis. Genes 2017, 8, 270. [Google Scholar] [CrossRef] [Green Version]
  101. 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. Stem Cells Transl. Med. 2017, 6, 613–621. [Google Scholar] [CrossRef] [PubMed]
  102. Pintat, J.; Silvestre, A.; Magalon, G.; Gadeau, A.P.; Pesquer, L.; Perozziello, A.; Peuchant, A.; Mounayer, C.; Dallaudière, B. Intra-articular injection of mesenchymal stem cells and platelet-rich plasma to treat patellofemoral osteoarthritis: Preliminary results of a long-term pilot study. J. Vasc. Interv. Radiol. 2017, 28, 1708–1713. [Google Scholar] [CrossRef] [PubMed]
  103. Russo, A.; Condello, V.; Madonna, V.; Guerriero, M.; Zorzi, C. Autologous and micro-fragmented adipose tissue for the treatment of diffuse degenerative knee osteoarthritis. J. Exp. Ortop. 2017, 4, 33. [Google Scholar] [CrossRef] [PubMed]
  104. Smyshlyaev, I.A.; Gilfanov, S.I.; Kopylov, V.A.; Gilmutdinov, R.G.; Pulin, I.I.; Korsakov, I.N.; Gilmutdinova, I.R.; Petrikina, A.P.; Eremin, P.S.; Kruchkova, O.V.; et al. Safety and effectiveness of intraarticular administration of adipose-derived stromal vascular fraction for treatment of knee articular cartilage degenerative damage: Preliminary results of a clinical trial. Traumatol. Orthop. Russ. 2017, 23, 17–31. [Google Scholar] [CrossRef] [Green Version]
  105. Yokota, N.; Yamakawa, M.; Shirata, T.; Kimura, T.; Kaneshima, H. Clinical results following intra-articular injection of adipose-derived stromal vascular fraction cells in patients with osteoarthritis of the knee. Regen. Ther. 2017, 6, 108–112. [Google Scholar] [CrossRef] [PubMed]
  106. Cattaneo, G.; De Caro, A.; Napoli, F.; Chiapale, D.; Trada, P.; Camera, A. Micro-fragmented adipose tissue injection associated with arthroscopic procedures in patients with symptomatic knee osteoarthritis. BMC Musculoskelet. Disord. 2018, 19, 176. [Google Scholar] [CrossRef]
  107. Cavallo, M.; Sayyed-Hosseinian, S.-H.; Parma, A.; Buda, R.; Mosca, M.; Giannini, S. Combination of high tibial osteotomy and autologous bone marrow derived cell implantation in early osteoarthritis of knee: A preliminary study. Arch. Bone Jt. Surg. 2018, 6, 112–118. [Google Scholar]
  108. Rodriguez-Fontan, F.; Piuzzi, N.S.; Kraeutler, M.J.; Pascual-Garrido, C. Early clinical outcomes of intra-articular injections of bone marrow aspirate concentrate for the treatment of early osteoarthritis of the hip and knee: A cohort study. PM&R 2018, 10, 1353–1359. [Google Scholar]
  109. Russo, A.; Screpis, D.; Di Donato, S.L.; Bonetti, S.; Piovan, G.; Zorzi, C. Autologous micro-fragmented adipose tissue for the treatment of diffuse degenerative knee osteoarthritis: An update at 3 year follow-up. J. Exp. Ortop. 2018, 5, 52. [Google Scholar] [CrossRef] [Green Version]
  110. Shaw, B.; Darrow, M.; Derian, A. Short-term outcomes in treatment of knee osteoarthritis with 4 bone marrow concentrate injections. Clin. Med. Insights Arthritis Musculoskelet. Disord. 2018, 11, 117954411878108. [Google Scholar] [CrossRef] [Green Version]
  111. Spasovski, D.; Spasovski, V.; Baščarević, Z.; Stojiljković, M.; Vreća, M.; Anđelković, M.; Pavlović, S. Intra-articular injection of autologous adipose-derived mesenchymal stem cells in the treatment of knee osteoarthritis. J. Gene Med. 2018, 20, e3002. [Google Scholar] [CrossRef] [PubMed]
  112. Themistocleous, G.S.; Chloros, G.D.; Kyrantzoulis, I.M.; Georgokostas, I.A.; Themistocleous, M.S.; Papagelopoulos, P.J.; Savvidou, O.D. Effectiveness of a single intra-articular bone marrow aspirate concentrate (bmac) injection in patients with Grade 3 and 4 knee osteoarthritis. Heliyon 2018, 4, e00871. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Borić, I.; Hudetz, D.; Rod, E.; Jeleč, Ž.; Vrdoljak, T.; Skelin, A.; Polašek, O.; Plečko, M.; Trbojević-Akmačić, I.; Lauc, G.; et al. A 24-month follow-up study of the effect of intra-articular injection of autologous microfragmented fat tissue on proteoglycan synthesis in patients with knee osteoarthritis. Genes 2019, 10, 1051. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Goncars, V.; Kalnberzs, K.; Jakobsons, E.; Enģele, I.; Briede, I.; Blums, K.; Erglis, K.; Erglis, M.; Patetko, L.; Muiznieks, I.; et al. Treatment of knee osteoarthritis with bone marrow–derived mononuclear cell injection: 12-month follow-up. Cartilage 2019, 10, 26–35. [Google Scholar] [CrossRef]
  115. Hudetz, D.; Borić, I.; Rod, E.; Jeleč, Ž.; Kunovac, B.; Polašek, O.; Vrdoljak, T.; Plečko, M.; Skelin, A.; Polančec, D.; et al. Early results of intra-articular micro-fragmented lipoaspirate treatment in patients with late stages knee osteoarthritis: A prospective study. Croat. Med. J. 2019, 60, 227–236. [Google Scholar] [CrossRef]
  116. Monckeberg, J.E.; Rafols, C.; Apablaza, F.; Gerhard, P.; Rosales, J. Intra-articular administration of peripheral blood stem cells with platelet-rich plasma regenerated articular cartilage and improved clinical outcomes for knee chondral lesions. Knee 2019, 26, 824–831. [Google Scholar] [CrossRef]
  117. Onoi, Y.; Hiranaka, T.; Nishida, R.; Takase, K.; Fujita, M.; Hida, Y.; Fujishiro, T.; Okamoto, K. Second-look arthroscopic findings of cartilage and meniscus repair after injection of adipose-derived regenerative cells in knee osteoarthrits: Report of two cases. Regen. Ther. 2019, 11, 212–216. [Google Scholar] [CrossRef]
  118. Roato, I.; Belisario, D.C.; Compagno, M.; Lena, A.; Bistolfi, A.; Maccari, L.; Mussano, F.; Genova, T.; Godio, L.; Perale, G.; et al. Concentrated adipose tissue infusion for the treatment of knee osteoarthritis: Clinical and histological observations. Int. Orthop. 2019, 43, 15–23. [Google Scholar] [CrossRef]
  119. Schiavone Panni, A.; Vasso, M.; Braile, A.; Toro, G.; De Cicco, A.; Viggiano, D.; Lepore, F. Preliminary results of autologous adipose-derived stem cells in early knee osteoarthritis: Identification of a subpopulation with greater response. Int. Orthop. 2019, 43, 7–13. [Google Scholar] [CrossRef]
  120. Song, J.-S.; Hong, K.-T.; Kim, N.-M.; Jung, J.-Y.; Park, H.-S.; Chun, Y.S.; Kim, S.J. Cartilage regeneration in osteoarthritic knees treated with distal femoral osteotomy and intra-lesional implantation of allogenic human umbilical cord blood-derived mesenchymal stem cells: A report of two cases. Knee 2019, 26, 1445–1450. [Google Scholar] [CrossRef]
  121. Wang, J.; Wright, K.T.; Perry, J.; Tins, B.; Hopkins, T.; Hulme, C.; McCarthy, H.S.; Brown, A.; Richardson, J.B. Combined autologous chondrocyte and bone marrow mesenchymal stromal cell implantation in the knee: An 8-year follow up of two first-in-man cases. Cell Transplant. 2019, 28, 924–931. [Google Scholar] [CrossRef] [PubMed]
  122. Colberg, R.E.; Jurado Vélez, J.A.; Walsh, K.P.; Fleisig, G. Short-term outcomes after pure bone marrow aspirate injection for severe knee osteoarthritis: A case series. Regen. Med. 2020, 15, 1851–1859. [Google Scholar] [CrossRef] [PubMed]
  123. Dilogo, I.H.; Canintika, A.F.; Hanitya, A.L.; Pawitan, J.A.; Liem, I.K.; Pandelaki, J. Umbilical cord-derived mesenchymal stem cells for treating osteoarthritis of the knee: A single-arm, open-label study. Eur. J. Orthop. Surg. Traumatol. 2020, 30, 799–807. [Google Scholar] [CrossRef] [PubMed]
  124. Dulic, O.; Lalic, I.; Kecojevic, V.; Gavrilovic, G.; Abazovic, D.; Miskulin, M.; Maric, D.; Bumbasirevic, M. Do knee injection portals affect clinical results of bone marrow aspirate concentrate injection in the treatment of osteoarthritis? a prospective randomized controlled study. Regen. Med. 2020, 15, 1987–2000. [Google Scholar] [CrossRef] [PubMed]
  125. Freitag, J.; Wickham, J.; Shah, K.; Li, D.; Norsworthy, C.; Tenen, A. Mesenchymal stem cell therapy combined with arthroscopic abrasion arthroplasty regenerates cartilage in patients with severe knee osteoarthritis: A case series. Regen. Med. 2020, 15, 1957–1977. [Google Scholar] [CrossRef]
  126. Heidari, N.; Noorani, A.; Slevin, M.; Cullen, A.; Stark, L.; Olgiati, S.; Zerbi, A.; Wilson, A. Patient-centered outcomes of microfragmented adipose tissue treatments of knee osteoarthritis: An observational, intention-to-treat study at twelve months. Stem Cells Int. 2020, 2020, 1–8. [Google Scholar] [CrossRef] [PubMed]
  127. Higuchi, J.; Yamagami, R.; Matsumoto, T.; Terao, T.; Inoue, K.; Tsuji, S.; Maenohara, Y.; Matsuzaki, T.; Chijimatsu, R.; Omata, Y.; et al. Associations of clinical outcomes and mri findings in intra-articular administration of autologous adipose-derived stem cells for knee osteoarthritis. Regen. Ther. 2020, 14, 332–340. [Google Scholar] [CrossRef]
  128. Kim, G.B.; Kim, J.-D.; Choi, Y.; Choi, C.H.; Lee, G.W. Intra-articular bone marrow aspirate concentrate injection in patients with knee osteoarthritis. Appl. Sci. 2020, 10, 5945. [Google Scholar] [CrossRef]
  129. Kim, Y.S.; Suh, D.S.; Tak, D.H.; Chung, P.K.; Koh, Y.G. Mesenchymal stem cell implantation in knee osteoarthritis: Midterm outcomes and survival analysis in 467 patients. Orthop. J. Sports Med. 2020, 8, 232596712096918. [Google Scholar] [CrossRef]
  130. Lapuente, J.P.; Dos-Anjos, S.; Blázquez-Martínez, A. Intra-articular infiltration of adipose-derived stromal vascular fraction cells slows the clinical progression of moderate-severe knee osteoarthritis: Hypothesis on the regulatory role of intra-articular adipose tissue. J. Orthop. Surg. Res. 2020, 15, 137. [Google Scholar] [CrossRef] [Green Version]
  131. Mehling, B.; Hric, M.; Salatkova, A.; Vetrak, R.; Santora, D.; Ovariova, M.; Mihalyova, R.; Manvelyan, M. A Retrospective study of stromal vascular fraction cell therapy for osteoarthritis. J. Clin. Med. Res. 2020, 12, 747–751. [Google Scholar] [CrossRef] [PubMed]
  132. Prodromos, C.; Finkle, S. Autologous biologic treatment with fat, bone marrow aspirate and platelet rich plasma is an effective alternative to total knee arthroplasty for patients with moderate knee arthrosis. Medicines 2020, 7, 37. [Google Scholar] [CrossRef] [PubMed]
  133. Song, J.-S.; Hong, K.-T.; Kim, N.-M.; Jung, J.-Y.; Park, H.-S.; Lee, S.H.; Cho, Y.J.; Kim, S.J. Implantation of allogenic umbilical cord blood-derived mesenchymal stem cells improves knee osteoarthritis outcomes: Two-year follow-up. Regen. Ther. 2020, 14, 32–39. [Google Scholar] [CrossRef] [PubMed]
  134. Song, J.-S.; Hong, K.-T.; Kim, N.-M.; Park, H.-S.; Choi, N.-H. Human umbilical cord blood-derived mesenchymal stem cell implantation for osteoarthritis of the knee. Arch. Orthop. Trauma Surg. 2020, 140, 503–509. [Google Scholar] [CrossRef] [PubMed]
  135. Song, J.-S.; Hong, K.-T.; Kong, C.-G.; Kim, N.-M.; Jung, J.-Y.; Park, H.-S.; Kim, Y.J.; Chang, K.B.; Kim, S.J. High tibial osteotomy with human umbilical cord blood-derived mesenchymal stem cells implantation for knee cartilage regeneration. World J. Stem Cells 2020, 12, 514–526. [Google Scholar] [CrossRef]
  136. Toan, D.D.; Binh, N.T.; Dung, T.T.; Thuy, L.Q.; Hoa, N.D.; Long, N.H.; Tung, P.S. The effectiveness of knee osteoarthritis treatment by arthroscopic microfracture technique in combination with autologous bone marrow stem cells transplantation. J. Back Musculoskelet. Rehabil. 2020, 33, 397–403. [Google Scholar] [CrossRef]
  137. Tsubosaka, M.; Matsumoto, T.; Sobajima, S.; Matsushita, T.; Iwaguro, H.; Kuroda, R. The influence of adipose-derived stromal vascular fraction cells on the treatment of knee osteoarthritis. BMC Musculoskelet. Disord. 2020, 21, 207. [Google Scholar] [CrossRef]
  138. Varady, N.H.; Cate, G.; Barghi, A.; Jobe, N.; Yakin, D.; Ylanan, R.C.; Arnold, C.A. Positive early clinical outcomes of bone marrow aspirate concentrate for osteoarthritis using a novel fenestrated trocar. Knee 2020, 27, 1627–1634. [Google Scholar] [CrossRef]
  139. Wells, K.; Klein, M.; Hurwitz, N.; Santiago, K.; Cheng, J.; Abutalib, Z.; Beatty, N.; Lutz, G. Cellular and clinical analyses of autologous bone marrow aspirate injectate for knee osteoarthritis: A pilot study. PM&R 2021, 13, 387–396. [Google Scholar]
  140. Bąkowski, P.; Kaszyński, J.; Baka, C.; Kaczmarek, T.; Ciemniewska-Gorzela, K.; Bąkowska-Żywicka, K.; Piontek, T. Patients with Stage II of the knee osteoarthritis most likely benefit from the intra-articular injections of autologous adipose tissue—From 2 years of follow-up studies. Arch. Orthop. Trauma Surg. 2021. [Google Scholar] [CrossRef]
  141. Borg, T.-M.; Heidari, N.; Noorani, A.; Slevin, M.; Cullen, A.; Olgiati, S.; Zerbi, A.; Danovi, A.; Wilson, A. Gender-specific response in pain and function to biologic treatment of knee osteoarthritis: A gender-bias-mitigated, observational, intention-to-treat study at two years. Stem Cells Int. 2021, 2021, 1–12. [Google Scholar] [CrossRef] [PubMed]
  142. Burnham, R.; Smith, A.; Hart, D. The safety and effectiveness of bone marrow concentrate injection for knee and hip osteoarthritis: A Canadian cohort. Regen. Med. 2021, 16, 619–628. [Google Scholar] [CrossRef] [PubMed]
  143. Caforio, M.; Nobile, C. Intra-articular administration of autologous purified adipose tissue associated with arthroscopy ameliorates knee osteoarthritis symptoms. J. Clin. Med. 2021, 10, 2053. [Google Scholar] [CrossRef] [PubMed]
  144. Heidari, N.; Borg, T.-M.; Olgiati, S.; Slevin, M.; Danovi, A.; Fish, B.; Wilson, A.; Noorani, A. Microfragmented adipose tissue injection (mfat) may be a solution to the rationing of total knee replacement: A prospective, gender-bias mitigated, reproducible analysis at two years. Stem Cells Int. 2021, 2021, 1–14. [Google Scholar] [CrossRef] [PubMed]
  145. Kim, Y.S.; Suh, D.S.; Tak, D.H.; Chung, P.K.; Kwon, Y.B.; Kim, T.Y.; Koh, Y.G. Factors influencing clinical and mri outcomes of mesenchymal stem cell implantation with concomitant high tibial osteotomy for varus knee osteoarthritis. Orthop. J. Sports Med. 2021, 9, 232596712097998. [Google Scholar] [CrossRef] [PubMed]
  146. Malanga, G.A.; Chirichella, P.S.; Hogaboom, N.S.; Capella, T. Clinical evaluation of micro-fragmented adipose tissue as a treatment option for patients with meniscus tears with osteoarthritis: A prospective pilot study. Int. Orthop. 2021, 45, 473–480. [Google Scholar] [CrossRef]
  147. Santoprete, S.; Marchetti, F.; Rubino, C.; Bedini, M.G.; Nasto, L.A.; Cipolloni, V.; Pola, E. Fresh autologous stromal tissue fraction for the treatment of knee osteoarthritis related pain and disability. Orthop. Rev. 2021, 13, 9161. [Google Scholar] [CrossRef]
  148. Sekiya, I.; Katano, H.; Mizuno, M.; Koga, H.; Masumoto, J.; Tomita, M.; Ozeki, N. Alterations in cartilage quantification before and after injections of mesenchymal stem cells into osteoarthritic knees. Sci. Rep. 2021, 11, 13832. [Google Scholar] [CrossRef] [PubMed]
  149. Van Genechten, W.; Vuylsteke, K.; Martinez, P.R.; Swinnen, L.; Sas, K.; Verdonk, P. Autologous micro-fragmented adipose tissue (MFAT) to treat symptomatic knee osteoarthritis: Early outcomes of a consecutive case series. J. Clin. Med. 2021, 10, 2231. [Google Scholar] [CrossRef]
  150. Centeno, C.J.; Busse, D.; Kisiday, J.; Keohan, C.; Freeman, M.; Karli, D. Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells. Pain Physician 2008, 11, 343–353. [Google Scholar]
  151. Centeno, C.J.; Busse, D.; Kisiday, J.; Keohan, C.; Freeman, M. Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells, platelet lysate and dexamethasone. Am. J. Case Rep. 2008, 9, 246–251. [Google Scholar]
  152. Mehrabani, D.; Mojtahed Jaberi, F.; Zakerinia, M.; Hadianfard, M.J.; Jalli, R.; Tanideh, N.; Zare, S. The healing effect of bone-marrow-derived stem cells in knee osteoarthritis: A case report. World J. Plast. Surg. 2016, 5, 168–174. [Google Scholar] [PubMed]
  153. Bright, B.; Bright, R.; Bright, P.; Limaye, A. Ankylosing spondylitis, chronic fatigue and depression improved after stromal vascular fraction treatment for osteoarthritis: A case report. J. Med. Case Rep. 2018, 12, 238. [Google Scholar] [CrossRef] [PubMed]
  154. Freitag, J.; Norsworthy, C.; Wickham, J.; Shah, K.; Tenen, A. High tibial osteotomy in combination with arthroscopic abrasion arthroplasty and autologous adipose-derived mesenchymal stem cell therapy in the treatment of advanced knee osteoarthritis. BMJ Case Rep. 2019, 12, bcr-2018-228003. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  155. 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. Osteoarthr. Cartil. 2002, 10, 199–206. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  156. Saw, K.-Y.; Anz, A.; Siew-Yoke Jee, C.; Merican, S.; Ching-Soong Ng, R.; Roohi, S.A.; Ragavanaidu, K. Articular cartilage regeneration with autologous peripheral blood stem cells versus hyaluronic acid: A randomized controlled trial. Arthroscopy 2013, 29, 684–694. [Google Scholar] [CrossRef] [PubMed]
  157. Akgun, I.; Unlu, M.C.; Erdal, O.A.; Ogut, T.; Erturk, M.; Ovali, E.; Kantarci, F.; Caliskan, G.; Akgun, Y. Matrix-induced autologous mesenchymal stem cell implantation versus matrix-induced autologous chondrocyte implantation in the treatment of chondral defects of the knee: A 2-year randomized study. Arch. Orthop. Trauma Surg. 2015, 135, 251–263. [Google Scholar] [CrossRef] [PubMed]
  158. Koh, Y.-G.; Kwon, O.-R.; Kim, Y.-S.; Choi, Y.-J.; Tak, D.-H. Adipose-derived mesenchymal stem cells with microfracture versus microfracture alone: 2-year follow-up of a prospective randomized trial. Arthroscopy 2016, 32, 97–109. [Google Scholar] [CrossRef] [PubMed]
  159. Shadmanfar, S.; Labibzadeh, N.; Emadedin, M.; Jaroughi, N.; Azimian, V.; Mardpour, S.; Kakroodi, F.A.; Bolurieh, T.; Hosseini, S.E.; Chehrazi, M.; et al. Intra-articular knee implantation of autologous bone marrow–derived mesenchymal stromal cells in rheumatoid arthritis patients with knee involvement: Results of a randomized, triple-blind, placebo-controlled Phase 1/2 clinical trial. Cytotherapy 2018, 20, 499–506. [Google Scholar] [CrossRef]
  160. de Girolamo, L.; Schönhuber, H.; Viganò, M.; Bait, C.; Quaglia, A.; Thiebat, G.; Volpi, P. Autologous matrix-induced chondrogenesis (AMIC) and AMIC enhanced by autologous concentrated bone marrow aspirate (BMAC) allow for stable clinical and functional improvements at up to 9 years follow-up: Results from a randomized controlled study. J. Clin. Med. 2019, 8, 392. [Google Scholar] [CrossRef] [Green Version]
  161. Hashimoto, Y.; Nishida, Y.; Takahashi, S.; Nakamura, H.; Mera, H.; Kashiwa, K.; Yoshiya, S.; Inagaki, Y.; Uematsu, K.; Tanaka, Y.; et al. Transplantation of autologous bone-marrow-derived mesenchymal stem cells under arthroscopic surgery with microfracture versus microfracture alone for articular cartilage lesions in the knee: A multicenter prospective randomized control clinical trial. Regen. Ther. 2019, 11, 106–113. [Google Scholar] [CrossRef]
  162. Olivos-Meza, A.; Pérez Jiménez, F.J.; Granados-Montiel, J.; Landa-Solís, C.; Cortés González, S.; Jiménez Aroche, C.A.; Valdez Chávez, M.; Renán León, S.; Gomez-Garcia, R.; Martínez-López, V.; et al. First clinical application of polyurethane meniscal scaffolds with mesenchymal stem cells and assessment of cartilage quality with T2 mapping at 12 months. Cartilage 2021, 13, 197S–207S. [Google Scholar] [CrossRef]
  163. Kim, Y.S.; Chung, P.K.; Suh, D.S.; Heo, D.B.; Tak, D.H.; Koh, Y.G. Implantation of mesenchymal stem cells in combination with allogenic cartilage improves cartilage regeneration and clinical outcomes in patients with concomitant high tibial osteotomy. Knee Surg. Sports Traumatol. Arthrosc. 2020, 28, 544–554. [Google Scholar] [CrossRef]
  164. Lim, H.-C.; Park, Y.-B.; Ha, C.-W.; Cole, B.J.; Lee, B.-K.; Jeong, H.-J.; Kim, M.-K.; Bin, S.-I.; Choi, C.-H.; Choi, C.H.; et al. Allogeneic umbilical cord blood–derived mesenchymal stem cell implantation versus microfracture for large, full-thickness cartilage defects in older patients: A multicenter randomized clinical trial and extended 5-year clinical follow-up. Orthop. J. Sports Med. 2021, 9, 232596712097305. [Google Scholar] [CrossRef]
  165. Saw, K.-Y.; Anz, A.W.; Ng, R.C.-S.; Jee, C.S.-Y.; Low, S.F.; Dorvault, C.; Johnson, K.B. Arthroscopic subchondral drilling followed by injection of peripheral blood stem cells and hyaluronic acid showed improved outcome compared to hyaluronic acid and physiotherapy for massive knee chondral defects: A randomized controlled trial. Arthroscopy 2021, 37, 2502–2517. [Google Scholar] [CrossRef]
  166. Gobbi, A.; Chaurasia, S.; Karnatzikos, G.; Nakamura, N. Matrix-induced autologous chondrocyte implantation versus multipotent stem cells for the treatment of large patellofemoral chondral lesions: A nonrandomized prospective trial. Cartilage 2015, 6, 82–97. [Google Scholar] [CrossRef] [Green Version]
  167. Gobbi, A.; Whyte, G.P. One-stage cartilage repair using a hyaluronic acid–based scaffold with activated bone marrow–derived mesenchymal stem cells compared with microfracture: Five-year follow-up. Am. J. Sports Med. 2016, 44, 2846–2854. [Google Scholar] [CrossRef]
  168. Martinčič, D.; Leban, J.; Filardo, G.; Busacca, M.; Barlič, A.; Veber, M.; Drobnič, M. Autologous chondrocytes versus filtered bone marrow mesenchymal stem/stromal cells for knee cartilage repair—A prospective study. Int. Orthop. 2021, 45, 931–939. [Google Scholar] [CrossRef]
  169. Ryu, D.J.; Jeon, Y.S.; Park, J.S.; Bae, G.C.; Kim, J.; Kim, M.K. Comparison of bone marrow aspirate concentrate and allogenic human umbilical cord blood derived mesenchymal stem cell implantation on chondral defect of knee: Assessment of clinical and magnetic resonance imaging outcomes at 2-year follow-up. Cell Transplant. 2020, 29, 963689720943581. [Google Scholar] [CrossRef]
  170. Kasemkijwattana, C.; Hongeng, S.; Kesprayura, S.; Rungsinaporn, V.; Chaipinyo, K.; Chansiri, K. Autologous bone marrow mesenchymal stem cells implantation for cartilage defects: Two cases report. J. Med. Assoc. Thail. 2011, 94, 395–400. [Google Scholar]
  171. Skowroński, J.; Skowroński, R.; Rutka, M. Cartilage lesions of the knee treated with blood mesenchymal stem cells—Results. Ortop. Traumatol. Rehabil. 2012, 14, 569–577. [Google Scholar]
  172. Buda, R.; Vannini, F.; Cavallo, M.; Baldassarri, M.; Luciani, D.; Mazzotti, A.; Pungetti, C.; Olivieri, A.; Giannini, S. One-step arthroscopic technique for the treatment of osteochondral lesions of the knee with bone-marrow-derived cells: Three years results. Musculoskelet. Surg. 2013, 97, 145–151. [Google Scholar] [CrossRef]
  173. Gobbi, A.; Karnatzikos, G.; Sankineani, S.R. One-step surgery with multipotent stem cells for the treatment of large full-thickness chondral defects of the knee. Am. J. Sports Med. 2014, 42, 648–657. [Google Scholar] [CrossRef]
  174. Zhou, S.-F.; Zhang, Z.; Zhong, X.; Ji, H.; Tang, Z.; Bai, J.; Yao, M.; Hou, J.; Zheng, M.; Wood, D.; et al. Matrix-induced autologous chondrocyte implantation for the treatment of chondral defects of the knees in Chinese patients. Drug Des. Devel. Ther. 2014, 8, 2439–2448. [Google Scholar] [CrossRef] [Green Version]
  175. Jiang, Y.; Cai, Y.; Zhang, W.; Yin, Z.; Hu, C.; Tong, T.; Lu, P.; Zhang, S.; Neculai, D.; Tuan, R.S.; et al. Human cartilage-derived progenitor cells from committed chondrocytes for efficient cartilage repair and regeneration. Stem Cells Transl. Med. 2016, 5, 733–744. [Google Scholar] [CrossRef]
  176. Sadlik, B.; Jaroslawski, G.; Gladysz, D.; Puszkarz, M.; Markowska, M.; Pawelec, K.; Boruczkowski, D.; Oldak, T. Knee cartilage regeneration with umbilical cord mesenchymal stem cells embedded in collagen scaffold using dry arthroscopy technique. Adv. Exp. Med. Biol. 2017, 1020, 113–122. [Google Scholar]
  177. Whitehouse, M.R.; Howells, N.R.; Parry, M.C.; Austin, E.; Kafienah, W.; Brady, K.; Goodship, A.E.; Eldridge, J.D.; Blom, A.W.; Hollander, A.P. Repair of torn avascular meniscal cartilage using undifferentiated autologous mesenchymal stem cells: From in vitro optimization to a first-in-human study. Stem Cells Transl. Med. 2017, 6, 1237–1248. [Google Scholar] [CrossRef] [Green Version]
  178. Kamei, N.; Ochi, M.; Adachi, N.; Ishikawa, M.; Yanada, S.; Levin, L.S.; Kamei, G.; Kobayashi, T. The safety and efficacy of magnetic targeting using autologous mesenchymal stem cells for cartilage repair. Knee Surg. Sports Traumatol. Arthrosc. 2018, 26, 3626–3635. [Google Scholar] [CrossRef]
  179. Shetty, A.; Kim, S.; Ahmed, S.; Trattnig, S.; Kim, S.; Jang, H. A cost-effective cell- and matrix-based minimally invasive single-stage chondroregenerative technique developed with validated vertical translation methodology. Ann. R. Coll. Surg. Engl. 2018, 100, 240–246. [Google Scholar] [CrossRef]
  180. Shimomura, K.; Yasui, Y.; Koizumi, K.; Chijimatsu, R.; Hart, D.A.; Yonetani, Y.; Ando, W.; Nishii, T.; Kanamoto, T.; Horibe, S.; et al. First-in-human pilot study of implantation of a scaffold-free tissue-engineered construct generated from autologous synovial mesenchymal stem cells for repair of knee chondral lesions. Am. J. Sports Med. 2018, 46, 2384–2393. [Google Scholar] [CrossRef]
  181. Gobbi, A.; Whyte, G.P. Long-term clinical outcomes of one-stage cartilage repair in the knee with hyaluronic acid–based scaffold embedded with mesenchymal stem cells sourced from bone marrow aspirate concentrate. Am. J. Sports Med. 2019, 47, 1621–1628. [Google Scholar] [CrossRef]
  182. Sekiya, I.; Koga, H.; Otabe, K.; Nakagawa, Y.; Katano, H.; Ozeki, N.; Mizuno, M.; Horie, M.; Kohno, Y.; Katagiri, K.; et al. Additional use of synovial mesenchymal stem cell transplantation following surgical repair of a complex degenerative tear of the medial meniscus of the knee: A case report. Cell Transplant. 2019, 28, 1445–1454. [Google Scholar] [CrossRef] [Green Version]
  183. Ciemniewska-Gorzela, K.; Bąkowski, P.; Naczk, J.; Jakob, R.; Piontek, T. Complex meniscus tears treated with collagen matrix wrapping and bone marrow blood injection: Clinical effectiveness and survivorship after a minimum of 5 years’ follow-up. Cartilage 2021, 13, 228S–238S. [Google Scholar] [CrossRef]
  184. Freitag, J.; Shah, K.; Wickham, J.; Li, D.; Norsworthy, C.; Tenen, A. Evaluation of autologous adipose-derived mesenchymal stem cell therapy in focal chondral defects of the knee: A pilot case series. Regen. Med. 2020, 15, 1703–1717. [Google Scholar] [CrossRef]
  185. Veber, M.; Vogler, J.; Knežević, M.; Barlič, A.; Drobnič, M. Combination of filtered bone marrow aspirate and biomimetic scaffold for the treatment of knee osteochondral lesions: Cellular and early clinical results of a single centre case series. Tissue Eng. Regen. Med. 2020, 17, 375–386. [Google Scholar] [CrossRef]
  186. Chung, Y.-W.; Yang, H.-Y.; Kang, S.-J.; Song, E.-K.; Seon, J.-K. Allogeneic umbilical cord blood-derived mesenchymal stem cells combined with high tibial osteotomy: A retrospective study on safety and early results. Int. Orthop. 2021, 45, 481–488. [Google Scholar] [CrossRef]
  187. Liu, H.-C.; Liu, T.-S.T.; Liu, Y.-L.; Wang, J.-H.; Chang, C.-H.; Shih, T.T.-F.; Lin, F.-H. Atelocollagen-embedded chondrocyte precursors as a treatment for grade-4 cartilage defects of the femoral condyle: A case series with up to 9-year follow-up. Biomolecules 2021, 11, 942. [Google Scholar] [CrossRef]
  188. Saris, T.F.F.; de Windt, T.S.; Kester, E.C.; Vonk, L.A.; Custers, R.J.H.; Saris, D.B.F. Five-Year Outcome of 1-stage cell-based cartilage repair using recycled autologous chondrons and allogenic mesenchymal stromal cells: A first-in-human clinical trial. Am. J. Sports Med. 2021, 49, 941–947. [Google Scholar] [CrossRef]
  189. Adachi, N.; Ochi, M.; Deie, M.; Ito, Y. Transplant of mesenchymal stem cells and hydroxyapatite ceramics to treat severe osteochondral damage after septic arthritis of the knee. J. Rheumatol. 2005, 32, 1615–1618. [Google Scholar]
  190. Kuroda, R.; Ishida, K.; Matsumoto, T.; Akisue, T.; Fujioka, H.; Mizuno, K.; Ohgushi, H.; Wakitani, S.; Kurosaka, M. Treatment of a full-thickness articular cartilage defect in the femoral condyle of an athlete with autologous bone-marrow stromal cells. Osteoarthr. Cartil. 2007, 15, 226–231. [Google Scholar] [CrossRef] [Green Version]
  191. Broyles, J.E.; O’Brien, M.A.; Stagg, M.P. Microdrilling surgery augmented with intra-articular bone marrow aspirate concentrate, platelet-rich plasma, and hyaluronic acid: A technique for cartilage repair in the knee. Arthrosc. Tech. 2017, 6, e201–e206. [Google Scholar] [CrossRef] [Green Version]
  192. Freitag, J.; Shah, K.; Wickham, J.; Boyd, R.; Tenen, A. The effect of autologous adipose derived mesenchymal stem cell therapy in the treatment of a large osteochondral defect of the knee following unsuccessful surgical intervention of osteochondritis dissecans—A case study. BMC Musculoskelet. Disord. 2017, 18, 298. [Google Scholar] [CrossRef]
  193. Freitag, J.; Li, D.; Wickham, J.; Shah, K.; Tenen, A. Effect of autologous adipose-derived mesenchymal stem cell therapy in the treatment of a post-traumatic chondral defect of the knee. BMJ Case Rep. 2017, 2017, bcr-2017-220852. [Google Scholar] [CrossRef] [Green Version]
  194. Leigheb, M.; Bosetti, M.; De Consoli, A.; Borrone, A.; Cannas, M.; Grassi, F. Chondral tissue engineering of the reumatoid knee with collagen matrix autologous chondrocytes implant. Acta Biomed. 2017, 88, 107–113. [Google Scholar]
  195. Chen, H.H.; Chen, Y.C.; Yu, S.N.; Lai, W.L.; Shen, Y.S.; Shen, P.C.; Lin, S.H.; Chang, C.H.; Lee, S.M. Infrapatellar fat pad-derived mesenchymal stromal cell product for treatment of knee osteoarthritis: A first-in-human study with evaluation of the potency marker. Cytotherapy 2022, 24, 72–85. [Google Scholar] [CrossRef]
  196. Furia, J.P.; Lundeen, M.; Hurd, J.L.; Pearce, D.A.; Alt, C.; Alt, E.U.; Schmitz, C.; Maffulli, N. Why and how to use the body’s own stem cells for regeneration in musculoskeletal disorders: A primer. J. Orthop. Surg. Res. 2022, 17, 36. [Google Scholar] [CrossRef]
  197. Lopa, S.; Colombini, A.; Moretti, M.; de Girolamo, L. Injective mesenchymal stem cell-based treatments for knee osteoarthritis: From mechanisms of action to current clinical evidences. Knee Surg. Sports Traumatol. Arthrosc. 2019, 27, 2003–2020. [Google Scholar] [CrossRef] [Green Version]
  198. Liberati, A.; Altman, D.G.; Tetzlaff, J.; Mulrow, C.; Gotzsche, P.C.; Ioannidis, J.P.A.; Clarke, M.; Devereaux, P.J.; Kleijnen, J.; Moher, D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: Explanation and elaboration. BMJ 2009, 339, b2700. [Google Scholar] [CrossRef] [Green Version]
  199. Jiang, P.; Mao, L.; Qiao, L.; Lei, X.; Zheng, Q.; Li, D. Efficacy and safety of mesenchymal stem cell injections for patients with osteoarthritis: A meta-analysis and review of RCTs. Arch. Orthop. Trauma Surg. 2021, 141, 1241–1251. [Google Scholar] [CrossRef]
  200. Qu, H.; Sun, S. Efficacy of mesenchymal stromal cells for the treatment of knee osteoarthritis: A meta-analysis of randomized controlled trials. J. Orthop. Surg. Res. 2021, 16, 11. [Google Scholar] [CrossRef]
  201. Ma, W.; Liu, C.; Wang, S.; Xu, H.; Sun, H.; Fan, X. Efficacy and safety of intra-articular injection of mesenchymal stem cells in the treatment of knee osteoarthritis: A systematic review and meta-analysis. Medicine 2020, 99, e23343. [Google Scholar] [CrossRef] [PubMed]
  202. Song, Y.; Zhang, J.; Xu, H.; Lin, Z.; Chang, H.; Liu, W.; Kong, L. Mesenchymal stem cells in knee osteoarthritis treatment: A systematic review and meta-analysis. J. Orthop. Translat. 2020, 24, 121–130. [Google Scholar] [CrossRef] [PubMed]
  203. Huang, R.; Li, W.; Zhao, Y.; Yang, F.; Xu, M. Clinical efficacy and safety of stem cell therapy for knee osteoarthritis: A meta-analysis. Medicine 2020, 99, e19434. [Google Scholar] [CrossRef] [PubMed]
  204. Cao, Z.; Li, Y.; Gao, F.; Wu, R.; Dou, P.; Wang, W.; Li, Q. Mesenchymal stem cells: A new choice for nonsurgical treatment of oa? results from a bayesian network meta-analysis. Biomed. Res. Int. 2021, 2021, 1–10. [Google Scholar] [CrossRef]
  205. Wei, Z.-J.; Wang, Q.-Q.; Cui, Z.-G.; Inadera, H.; Jiang, X.; Wu, C.-A. Which is the most effective one in knee osteoarthritis treatment from mesenchymal stem cells obtained from different sources?—A systematic review with conventional and network meta-analyses of randomized controlled trials. Ann. Transl. Med. 2021, 9, 452. [Google Scholar] [CrossRef]
  206. Wang, J.; Zhou, L.; Zhang, Y.; Huang, L.; Shi, Q. Mesenchymal stem cells—A promising strategy for treating knee osteoarthritis: A meta-analysis. Bone Joint Res. 2020, 9, 719–728. [Google Scholar] [CrossRef]
  207. Bolia, I.K.; Bougioukli, S.; Hill, W.J.; Trasolini, N.A.; Petrigliano, F.A.; Lieberman, J.R.; Weber, A.E. Clinical efficacy of bone marrow aspirate concentrate versus stromal vascular fraction injection in patients with knee osteoarthritis: A systematic review and meta-analysis. Am. J. Sports Med. 2021, 036354652110145. [Google Scholar] [CrossRef]
  208. Jeyaraman, M.; Muthu, S.; Ganie, P.A. Does the source of mesenchymal stem cell have an effect in the management of osteoarthritis of the knee? meta-analysis of randomized controlled trials. Cartilage 2021, 13, 1532S–1547S. [Google Scholar] [CrossRef]
  209. Han, X.; Yang, B.; Zou, F.; Sun, J. Clinical therapeutic efficacy of mesenchymal stem cells derived from adipose or bone marrow for knee osteoarthritis: A meta-analysis of randomized controlled trials. J. Comp. Eff. Res. 2020, 9, 361–374. [Google Scholar] [CrossRef]
  210. Agarwal, N.; Mak, C.; Bojanic, C.; To, K.; Khan, W. Meta-analysis of adipose tissue derived cell-based therapy for the treatment of knee osteoarthritis. Cells 2021, 10, 1365. [Google Scholar] [CrossRef]
  211. Zhao, D.; Pan, J.; Yang, W.; Han, Y.; Zeng, L.; Liang, G.; Liu, J. Intra-articular injections of platelet-rich plasma, adipose mesenchymal stem cells, and bone marrow mesenchymal stem cells associated with better outcomes than hyaluronic acid and saline in knee osteoarthritis: A systematic review and network meta-analysis. Arthroscopy 2021, 37, 2298–2314. [Google Scholar] [CrossRef] [PubMed]
  212. Tan, S.H.S.; Kwan, Y.T.; Neo, W.J.; Chong, J.Y.; Kuek, T.Y.J.; See, J.Z.F.; Wong, K.L.; Toh, W.S.; Hui, J.H.P. Intra-articular injections of mesenchymal stem cells without adjuvant therapies for knee osteoarthritis: A systematic review and meta-analysis. Am. J. Sports Med. 2021, 49, 3113–3124. [Google Scholar] [CrossRef] [PubMed]
  213. Kim, S.H.; Djaja, Y.P.; Park, Y.-B.; Park, J.-G.; Ko, Y.-B.; Ha, C.-W. Intra-articular injection of culture-expanded mesenchymal stem cells without adjuvant surgery in knee osteoarthritis: A systematic review and meta-analysis. Am. J. Sports Med. 2020, 48, 2839–2849. [Google Scholar] [CrossRef] [PubMed]
  214. Ding, W.; Xu, Y.; Zhang, Y.; Li, A.; Qiu, X.; Wen, H.; Tan, H. Efficacy and safety of intra-articular cell-based therapy for osteoarthritis: Systematic review and network meta-analysis. Cartilage 2021, 13, 104S–115S. [Google Scholar] [CrossRef]
  215. Maheshwer, B.; Polce, E.M.; Paul, K.; Williams, B.T.; Wolfson, T.S.; Yanke, A.; Verma, N.N.; Cole, B.J.; Chahla, J. Regenerative potential of mesenchymal stem cells for the treatment of knee osteoarthritis and chondral defects: A systematic review and meta-analysis. Arthroscopy 2021, 37, 362–378. [Google Scholar] [CrossRef]
  216. Dai, W.; Leng, X.; Wang, J.; Shi, Z.; Cheng, J.; Hu, X.; Ao, Y. Intra-articular mesenchymal stromal cell injections are no different from placebo in the treatment of knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials. Arthroscopy 2021, 37, 340–358. [Google Scholar] [CrossRef]
  217. Han, S.-B.; Seo, I.-W.; Shin, Y.-S. Intra-articular injections of hyaluronic acid or steroids associated with better outcomes than platelet-rich plasma, adipose mesenchymal stromal cells, or placebo in knee osteoarthritis: A network meta-analysis. Arthroscopy 2021, 37, 292–306. [Google Scholar] [CrossRef]
  218. Vangsness, C.T.; Farr, J.; Boyd, J.; Dellaero, D.T.; Mills, C.R.; LeRoux-Williams, M. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: A randomized, double-blind, controlled study. J. Bone Joint Surg. 2014, 96, 90–98. [Google Scholar] [CrossRef] [Green Version]
  219. Bhattacharya, N. Clinical use of amniotic fluid in osteoarthritis: A source of cell therapy. Transplantation 2011, 90, 395–403. [Google Scholar]
  220. Lv, X.X.; Huang, C.; Yin, Z.; Hong, B.G.; Jiang, H.J.; Huang, X.J. Effectiveness of autologous bone marrow mesenchymal stem cell transplant for knee osteoarthritis. Chin. J. Cell Stem. Cell. 2015, 5, 28–32. [Google Scholar]
  221. Ha, C.Z.; Li, W.; Ren, S.D.; Zhou, C.H.; Chen, S.F.; Wang, D.W.; Liu, C. Effect of platelet rich plasma combined with mesenchymal stem cells in treatment of knee osteoarthritis. Chin. J. Joint Surg. (Electron. Ed.) 2018, 12, 644–652. [Google Scholar]
  222. Dieppe, P.; Goldingay, S.; Greville-Harris, M. The power and value of placebo and nocebo in painful osteoarthritis. Osteoarthr. Cartil. 2016, 24, 1850–1857. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  223. Zhang, W. The powerful placebo effect in osteoarthritis. Clin. Exp. Rheumatol. 2019, 37 (Suppl. 120), 118–123. [Google Scholar] [PubMed]
  224. Previtali, D.; Merli, G.; Di Laura Frattura, G.; Candrian, C.; Zaffagnini, S.; Filardo, G. The long-lasting effects of “placebo injections” in knee osteoarthritis: A meta-analysis. Cartilage 2021, 13, 185S–196S. [Google Scholar] [CrossRef]
  225. Winnier, G.E.; Valenzuela, N.; Peters-Hall, J.; Kellner, J.; Alt, C.; Alt, E.U. Isolation of adipose tissue derived regenerative cells from human subcutaneous tissue with or without the use of an enzymatic reagent. PLoS ONE 2019, 14, e0221457. [Google Scholar] [CrossRef] [Green Version]
  226. Alt, E.U.; Winnier, G.; Haenel, A.; Rothoerl, R.; Solakoglu, O.; Alt, C.; Schmitz, C. Towards a comprehensive understanding of ua-adrcs (uncultured, autologous, fresh, unmodified, adipose derived regenerative cells, isolated at point of care) in regenerative medicine. Cells 2020, 9, 1097. [Google Scholar] [CrossRef]
  227. Kozlowska, U.; Krawczenko, A.; Futoma, K.; Jurek, T.; Rorat, M.; Patrzalek, D.; Klimczak, A. Similarities and differences between mesenchymal stem/progenitor cells derived from various human tissues. World J. Stem Cells 2019, 11, 347–374. [Google Scholar] [CrossRef]
  228. Srivastava, M.; Ahlawat, N.; Srivastava, A. Amniotic fluid stem cells: A new era in regenerative medicine. J. Obstet. Gynecol. India 2018, 68, 15–19. [Google Scholar] [CrossRef]
  229. Higgins, J.P.T.; Thomas, J. Cochrane Handbook for Systematic Reviews of Interventions, 2nd ed.; Higgins, J.P.T., Thomas, J., Eds.; John Wiley & Sons: Hoboken, NJ, USA, 2008. [Google Scholar]
  230. Heitjan, D.F. Ignorability and bias in clinical trials. Statist. Med. 1999, 18, 2421–2434. [Google Scholar] [CrossRef]
  231. Panés, J.; García-Olmo, D.; Van Assche, G.; Colombel, J.F.; Reinisch, W.; Baumgart, D.C.; Dignass, A.; Nachury, M.; Ferrante, M.; Kazemi-Shirazi, L.; et al. Expanded allogeneic adipose-derived mesenchymal stem cells (cx601) for complex perianal fistulas in crohn’s disease: A Phase 3 randomised, double-blind controlled trial. Lancet 2016, 388, 1281–1290. [Google Scholar] [CrossRef]
  232. Álvaro-Gracia, J.M.; Jover, J.A.; García-Vicuña, R.; Carreño, L.; Alonso, A.; Marsal, S.; Blanco, F.; Martínez-Taboada, V.M.; Taylor, P.; Martín-Martín, C.; et al. Intravenous administration of expanded allogeneic adipose-derived mesenchymal stem cells in refractory rheumatoid arthritis (Cx611): Results of a multicentre, dose escalation, randomised, single-blind, placebo-controlled Phase Ib/IIa clinical trial. Ann. Rheum. Dis. 2017, 76, 196–202. [Google Scholar] [CrossRef] [PubMed]
  233. Kastrup, J.; Haack-Sørensen, M.; Juhl, M.; Harary Søndergaard, R.; Follin, B.; Drozd Lund, L.; Mønsted Johansen, E.; Ali Qayyum, A.; Bruun Mathiasen, A.; Jørgensen, E.; et al. Cryopreserved off-the-shelf allogeneic adipose-derived stromal cells for therapy in patients with ischemic heart disease and heart failure—A safety study. Stem Cells Transl. Med. 2017, 6, 1963–1971. [Google Scholar] [CrossRef] [PubMed]
  234. Marks, P.W.; Witten, C.M.; Califf, R.M. Clarifying stem-cell therapy’s benefits and risks. N. Engl. J. Med. 2017, 376, 1007–1009. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  235. Eder, C.; Schmidt-Bleek, K.; Geissler, S.; Sass, F.A.; Maleitzke, T.; Pumberger, M.; Perka, C.; Duda, G.N.; Winkler, T. Mesenchymal stromal cell and bone marrow concentrate therapies for musculoskeletal indications: A concise review of current literature. Mol. Biol. Rep. 2020, 47, 4789–4814. [Google Scholar] [CrossRef] [PubMed]
  236. Zhong, Y.C.; Wang, S.C.; Han, Y.H.; Wen, Y. Recent advance in source, property, differentiation, and applications of infrapatellar fat pad adipose-derived stem cells. Stem Cells Int. 2020, 2020, 2560174. [Google Scholar] [CrossRef] [PubMed]
  237. Vahedi, P.; Moghaddamshahabi, R.; Webster, T.J.; Calikoglu Koyuncu, A.C.; Ahmadian, E.; Khan, W.S.; Jimale Mohamed, A.; Eftekhari, A. The use of infrapatellar fat pad-derived mesenchymal stem cells in articular cartilage regeneration: A review. Int. J. Mol. Sci. 2021, 22, 9215. [Google Scholar] [CrossRef]
  238. Stocco, E.; Barbon, S.; Piccione, M.; Belluzzi, E.; Petrelli, L.; Pozzuoli, A.; Ramonda, R.; Rossato, M.; Favero, M.; Ruggieri, P.; et al. Infrapatellar fat pad stem cells responsiveness to microenvironment in osteoarthritis: From morphology to function. Front. Cell Dev. Biol. 2019, 7, 323. [Google Scholar] [CrossRef]
Cells 11 00965 g001 550
Figure 1. Systematic review flow chart of the first literature search regarding meta-analyses of clinical studies on the treatment of primary knee osteoarthritis with stem cells that were published between January 2020 and July 2021, performed according to the PRISMA guidelines [198] on 7 August 2021.
Figure 1. Systematic review flow chart of the first literature search regarding meta-analyses of clinical studies on the treatment of primary knee osteoarthritis with stem cells that were published between January 2020 and July 2021, performed according to the PRISMA guidelines [198] on 7 August 2021.
Cells 11 00965 g001
Cells 11 00965 g002 550
Figure 2. Systematic review flow chart of the second literature search regarding treatment of primary knee osteoarthritis with stem cells, performed according to the PRISMA guidelines [198] on 7 August 2021. Abbreviations: BMAC, bone marrow concentrate; ADRCs, adipose-derived regenerative cells; BM-MSCs, bone-marrow-derived mesenchymal stem cells; ADSCs, adipose-derived stem cells; MFF, micro-fragmented fat (from liposuction); and pBSCs, activated peripheral blood stem cells.
Figure 2. Systematic review flow chart of the second literature search regarding treatment of primary knee osteoarthritis with stem cells, performed according to the PRISMA guidelines [198] on 7 August 2021. Abbreviations: BMAC, bone marrow concentrate; ADRCs, adipose-derived regenerative cells; BM-MSCs, bone-marrow-derived mesenchymal stem cells; ADSCs, adipose-derived stem cells; MFF, micro-fragmented fat (from liposuction); and pBSCs, activated peripheral blood stem cells.
Cells 11 00965 g002
Table
Table 1. Categories of studies included in the 19 meta-analyses summarized in Table S2, which details clinical studies in which management of primary knee osteoarthritis with stem cells was investigated.
Table 1. Categories of studies included in the 19 meta-analyses summarized in Table S2, which details clinical studies in which management of primary knee osteoarthritis with stem cells was investigated.
CNallDescription
I8Intra-articular injection of stem cells as the sole treatment (not considering rehabilitation) compared with i.a. injection of saline or sham treatment as control.
II6Intra-articular injection of stem cells as the sole treatment (not considering rehabilitation) compared with i.a. injection of, respectively, PRP, CS or HA as control.
III10Intra-articular injection of stem cells as the sole treatment (not considering rehabilitation) compared with other treatments than those in Categories I and II as control.
IV12Combinations of i.a. injection of stem cells with other modalities compared with sham treatment or other treatments as control.
V13Combinations of i.a. injection of stem cells with or without other modalities without control group (case series or case reports).
VI4Treatment of focal chondral, osteochondral, or meniscal chondral lesions with stem cells as the sole treatment (not considering rehabilitation) or combinations of stem cells and other modalities with or without other treatments as control.
VII1Treatments that did not comprise stem cells.
VIII2Study not listed in PubMed, Embase, Web of Science, Cochrane Library, or Google Scholar.
Sum56
Abbreviations: C, category; Nall, number of studies among all studies included in the 19 assessed meta-analyses; pkOA, primary knee osteoarthritis; i.a., intra-articular; PRP, platelet-rich plasma; CS, corticosteroid; and HA, hyaluronic acid.
Table
Table 2. Types of studies included in the meta-analyses summarized in Table S2, which details clinical studies in which management of primary knee osteoarthritis with stem cells was investigated.
Table 2. Types of studies included in the meta-analyses summarized in Table S2, which details clinical studies in which management of primary knee osteoarthritis with stem cells was investigated.
TypeNallNpkOADescription
a2925Randomized controlled trials (RCTs)
b33RCTs with the contralateral knee as internal control
c77Prospective cohort studies
d22Retrospective cohort studies
e1313Case series with more than one subject
f00Case reports with only one subject
N22Study not listed in PubMed, Embase, Web of Science, Cochrane Library, or Google Scholar
Sum5652
Abbreviations: Nall, number of studies among all studies included in the 19 assessed meta-analyses and NpkOA, number of studies among those studies included in the 19 assessed meta-analyses that addressed pkOA.
Table
Table 3. Cell types used in those studies included in the meta-analyses summarized in Table S2 in which treatment of primary knee osteoarthritis with stem cells was investigated.
Table 3. Cell types used in those studies included in the meta-analyses summarized in Table S2 in which treatment of primary knee osteoarthritis with stem cells was investigated.
Cell TypeONallNpkOADescription
ADRCsAuto99Autologous, adipose-derived regenerative cells
ADSCsAuto1111Autologous, adipose-derived stem cells (obtained by culturing ADRCs)
ADSCsAllo11Allogeneic, adipose-derived stem cells
MFFAuto44Autologous, micro-fragmented fat (from liposuction)
CLLAuto11Autologous, centrifuged liposuction liquid
BMACAuto77Autologous bone marrow concentrate
BM-MSCsAuto109Autologous, bone-marrow-derived mesenchymal stem cells
BM-MSCsAllo32Allogeneic, bone-marrow-derived mesenchymal stromal cells
S-MSCsAuto10Autologous, matrix-induced MSCs from synovia
Ch-TGFβAllo22Allogeneic chondrocytes that overexpress transforming growth factor beta
hUC-MSCsAllo22Allogeneic, human-umbilical-cord-derived MSCs
P-MSCsAllo11Allogeneic, placental MSCs
pBMCsAuto10Autologous, activated peripheral blood stem cells
No cellsAllo11Allogeneic amniotic fluid
Sum 5450
Abbreviations: Nall, number of studies among all studies included in the 19 assessed meta-analyses and NpkOA, number of studies among those studies included in the 19 assessed meta-analyses that addressed pkOA.
Table
Table 4. Type of analysis performed in the meta-analyses summarized in Table S2 in which treatment of primary knee osteoarthritis with stem cells was investigated.
Table 4. Type of analysis performed in the meta-analyses summarized in Table S2 in which treatment of primary knee osteoarthritis with stem cells was investigated.
CNDescription
112Meta-analysis of studies in which treatment of pkOA with stem cells was compared with placebo treatment (or studies in which treatment of pkOA with stem cells plus concomitant therapy was compared with the concomitant therapy alone, respectively).
24Meta-analysis in which only endpoints of the same patients before and after treatment were compared.
33Network meta-analysis that included only a small number of studies on the treatment of pkOA with stem cells and a much higher number of studies on the treatment of pkOA without stem cells.
Sum19
Abbreviations: C, category; N, number of meta-analyses; i.a., intra-articular; pkOA, primary knee osteoarthritis; PRP, platelet rich plasma; CS, corticosteroid; and HA, hyaluronic acid.
Table
Table 5. Criteria used to assess the quality of sub-analyses in the meta-analyses summarized in Table S2 of studies in which treatment of primary knee osteoarthritis with different types of stem cells was investigated.
Table 5. Criteria used to assess the quality of sub-analyses in the meta-analyses summarized in Table S2 of studies in which treatment of primary knee osteoarthritis with different types of stem cells was investigated.
No. NaNr [%]
1At least 2 different clinical studies were included.14189.8
2Only clinical studies on pkOA were included.14189.8
3Only clinical studies in which stem cells were applied were included.15598.7
4Only randomized controlled trials were included.13384.7
5Only clinical studies were included in which application of stem cells was compared with placebo treatment or in which application of stem cells plus concomitant therapy (including arthroscopic debridement, high tibial osteotomy, injection of hyaluronic acid, etc.) was compared with the concomitant therapy alone, respectively.5535.0
6Only clinical studies using, respectively, autologous or allogeneic stem cells were included.6440.8
7Only clinical studies in which, respectively, cultured or uncultured cells were applied were included.13384.7
8Clinical studies in which more than 1 dose of stem cells was applied were only considered once in the corresponding meta-analysis.10063.7
Abbreviations: Na and Nr, absolute (NA) and relative (NR) number of sub-analyses that fulfilled the corresponding criterion; No., number of criteria; and pkOA, primary knee osteoarthritis.
Table
Table 6. Categories of studies on treatment of primary knee osteoarthritis with stem cells that were identified during an evidence-based, systematic review of the literature according to the PRISMA guidelines [198] performed on 7 August 2021 (summarized in Table S1).
Table 6. Categories of studies on treatment of primary knee osteoarthritis with stem cells that were identified during an evidence-based, systematic review of the literature according to the PRISMA guidelines [198] performed on 7 August 2021 (summarized in Table S1).
CNallDescription
I8Treatment of pkOA with i.a. injection of stem cells as the sole treatment (not considering rehabilitation) compared with i.a. injection of saline or sham treatment as control.
II8Treatment of pkOA with i.a. injection of stem cells as the sole treatment (not considering rehabilitation) compared with i.a. injection of, respectively, PRP, CS or HA as control.
III22Treatment of pkOA with i.a. injection of stem cells as the sole treatment (not considering rehabilitation) compared with other treatments than those in Categories I and II as control.
IV27Treatment of pkOA with combinations of stem cells and other modalities compared with sham treatment or other treatments as control.
V78Treatment of pkOA with combinations of stem cells with or without other modalities without control group (case series or case reports).
VI40Treatment of focal chondral, osteochondral, or meniscal chondral lesions with stem cells as the sole treatment (not considering rehabilitation) or combinations of stem cells and other modalities with or without other treatments as control.
Sum183
Abbreviations: C, category; N, number of studies; i.a., intra-articular; pkOA, primary knee osteoarthritis; PRP, platelet rich plasma; CS, corticosteroid; and HA, hyaluronic acid.
Table
Table 7. Types of studies on treatment of primary knee osteoarthritis with stem cells that were identified during an evidence-based, systematic review of the literature according to the PRISMA guidelines [198] performed on 7 August 2021.
Table 7. Types of studies on treatment of primary knee osteoarthritis with stem cells that were identified during an evidence-based, systematic review of the literature according to the PRISMA guidelines [198] performed on 7 August 2021.
TypeNallNpkOADescription
a4433Randomized controlled trials (RCTs)
b66RCTs with the contralateral knee as internal control
c1815Prospective cohort studies
d1211Retrospective cohort studies
e9273Case series with more than one subject
f115Case reports with only one subject
Sum183143
Abbreviations: Nall, number of studies among all studies listed in Table S1, and NpkOA, number of studies among those studies listed in Table S1 that addressed primary knee osteoarthritis (pkOA).
Table
Table 8. Types of stem cells used in studies on management of primary knee osteoarthritis with stem cells that were identified during an evidence-based, systematic review of the literature according to the PRISMA guidelines [198] performed on 7 August 2021.
Table 8. Types of stem cells used in studies on management of primary knee osteoarthritis with stem cells that were identified during an evidence-based, systematic review of the literature according to the PRISMA guidelines [198] performed on 7 August 2021.
Cell TypeNallNpkOADescription
ADRCs3635Adipose-derived regenerative cells
ADSCs2218Adipose-derived stem cells (obtained by culturing ADRCs)
MFF2121Micro-fragmented fat (from liposuction)
CLL11Centrifuged liposuction liquid
BMA11Bone marrow aspirate
BMAC3826Bone marrow aspirate concentrate
BM-MSCs3425Bone-marrow-derived mesenchymal stem cells
Cs/CPs20Chondrocytes and chondrocyte precursors
CSCs10Cartilage stem cells
MACI10Matrix-induced, autologous chondrocyte implant
S-MSCs41Matrix-induced MSCs from synovia
Ch-TGFβ22Chondrocytes that overexpress transforming growth factor beta
hUC-MSCs43Human-umbilical-cord-derived MSCs
hUCB-MSCs76Human-umbilical-cord-blood-derived MSCs
P-MSCs11Placental MSCs
pBSCs84Activated peripheral blood stem cells
Sum183143
Abbreviations: Nall, number of studies among all studies listed in Table S1, and NpkOA, number of studies among those studies listed in Table S1 that addressed primary knee osteoarthritis (pkOA).
Table
Table 9. Detailed analysis of clinical studies on the management of primary knee osteoarthritis with stem cells (summarized in Table S1) that were identified during an evidence-based, systematic review of the literature according to the PRISMA guidelines [198] performed on 7 August 2021. The categories of studies (I to VI) are explained in Table 6 and the types of study (a to f) in Table 7.
Table 9. Detailed analysis of clinical studies on the management of primary knee osteoarthritis with stem cells (summarized in Table S1) that were identified during an evidence-based, systematic review of the literature according to the PRISMA guidelines [198] performed on 7 August 2021. The categories of studies (I to VI) are explained in Table 6 and the types of study (a to f) in Table 7.
CategoryType of StudyADRCsADSCsMFFCLLBMABMACBM-MSCsCs/CPsCSCsMACIS-MSCsCh-TGFβhUC-MSCshUCB-MSCsP-MSCspBSCsSum
Ia12 1 2 1 7
b 1 1
c 0
d 0
IIa 11 21 2 7
b 0
c 0
d1 1
IIIa 4 11 6
b 3 3
c152 1 9
d2 1 1 4
IVa211 17 113
b1 1 2
c51 6
d1 1 4 6
Ve20315111311 1 15 274
f11 2 4
VIa11 13 1 1 311
b 0
c 3 3
d 1 1
e 1 641112 111 19
f 2 121 6
NpkOA 156834614892032588385 81287518610546860
NCL 4022 3178313151518 *166 129818
General abbreviations: NpkOA, number of patients with primary knee osteoarthritis treated in these studies; NCL, number of patients with chondral lesions treated in these studies; and *, number of patients not provided. Abbreviations of cell types: ADRCs, adipose-derived regenerative cells; ADSCs, adipose-derived stem cells (obtained by culturing ADRCs); MFF, micro-fragmented fat (from liposuction); CLL; centrifuged liposuction liquid; BMA, bone marrow aspirate; BMAC, bone marrow aspirate concentrate; BM-MSCs, bone-marrow-derived mesenchymal stromal cells; Cs, chondrocytes; CPs, chondrocyte precursors; CSCs, cartilage stem cells; MACI; matrix-induced autologous chondrocyte implant; S-MSCs, matrix-induced MSCs from synovia; hUC-MSCs, human umbilical cord-derived MSCs; hUCB-MSCs, human umbilical cord blood-derived MSCs; P-MSCs, placental MSCs; and pBSCs, activated peripheral blood stem cells.
Table
Table 10. Sub-analyses that would generally be possible in a meta-analysis of studies on treatment of primary knee osteoarthritis with stem cells (summarized in Table S1) that were identified during an evidence-based, systematic review of the literature according to the PRISMA guidelines [198] performed on 7 August 2021.
Table 10. Sub-analyses that would generally be possible in a meta-analysis of studies on treatment of primary knee osteoarthritis with stem cells (summarized in Table S1) that were identified during an evidence-based, systematic review of the literature according to the PRISMA guidelines [198] performed on 7 August 2021.
RCTFirst AuthorYCell TypeTreatmentControl
Autologous, uncultured cells
[19]1aGarza2020ADRCsCRS
[52]4aKoh2014ADRCsC + AD + HTO + PRPAD + HTO + PRP
[58]4aPeretti2018MFFC + ADAD
Autologous, cultured cells
[18]1aLee2019ADSCsCSa
[30]3aFreitag2019ADSCsCCM
[56]4aZhang2018ADSCsC + HAC
[60]4aQiao2020ADSCsC + AD + MF + HAMF or MF + HA
[14]1aEmamedin2018BM-MSCsCSa
[50]4aVarma2010BM-MSCsC + ADAD
[51]4aWong2013BM-MSCsC + MF + HTO + HAMF + HA + HTO
[53]4aLamo-Espinosa2016BM-MSCsC + HAHA
[55]4aBastos2018BM-MSCsC + PRPC
[57]4aLamo-Espinosa2018BM-MSCsC + HAHA
[59]4aLamo-Espinosa2020BM-MSCsC + PRPPRP
Allogeneic, cultured cells
[12]1aCherian2015Ch-TGFßCSa
[13]4aGupta2016BM-MSCsC + HASa + HA
[15]1aKim2018Ch-TGFßCSa
[16]1aKuah2018ADSCsCSa
[17]1aKhalifeh Soltani2019P-MSCsCSa
General abbreviations: R, reference number; C, category of study as outlined in Table 6; T, type of study as outlined in Table 6; and Y, year of publication. Abbreviations of cell types (in alphabetical order): ADRCs, adipose-derived regenerative cells; ADSCs, adipose-derived stem cells; BM-MSCs, bone-marrow-derived mesenchymal stromal cells; Ch-TGFß, chondrocytes that overexpress transcription growth factor beta; MFF, micro-fragmented fat; P-MSCs, placental MSCs. Abbreviations of treatments (in alphabetical order): AD, arthroscopic debridement; C, cells; HTO, high tibial osteotomy; MF, microfracture; RS, Ringer solution; PRP, platelet rich plasma; and Sa, saline.
Table
Table 11. Reported outcome in studies on treatment of primary knee osteoarthritis with autologous, adipose-derived regenerative cells, or autologous, adipose-derived stem cells listed in Table 10.
Table 11. Reported outcome in studies on treatment of primary knee osteoarthritis with autologous, adipose-derived regenerative cells, or autologous, adipose-derived stem cells listed in Table 10.
RFAReported Outcome
Autologous ADRCs
[19]Garza
  • WOMAC total score at BL and at W6, M3, M6 and M12 (mean, median, interquartile range, median percentage range, minimum, maximum)
  • Cartilage loss (mean at BL, mean change at M6)
  • Outerbridge classification (median at BL, range at BL, median change at M6)
[52]Koh
  • VAS pain score (mean and SD at baseline and at last follow-up)
  • KOOS sub-scores (mean improvement from BL to LFU)
  • Lysholm score (mean and SD at BL and LFU)
  • Weight-bearing line (%) (mean and SD at BL and LFU)
  • Femorotibial angle (°) (mean and SD at BL and LFU)
Autologous ADSCs
[18]Lee
  • VAS pain score at BL, M3 and M6 (mean)
  • WOMAC total and sub-scores at BL, M3 and M6 (mean)
  • KOOS sub-scores at BL, M3 and M6 (mean)
  • Size of cartilage defect in MRI at BL and M6 (mean, SD)
[30]Freitag
  • VAS pain score at BL, M1,5, M3, M6 and M12 (mean, 95% CI)
  • KOOS sub-scores at BL, M1,5, M3, M6 and M12 (mean, 95% CI)
  • WOMAC score at BL, M1,5, M3, M6 and M12 (mean, 95% CI)
[56]Zhang
  • VAS pain score at BL, M3, M6, M12, M24 and M36 (mean, SD)
  • WOMAC total score at BL, M3, M6, M12, M24 and M36 (mean, SD)
[60]Qiao
  • SF-36 Physical Component and Mental Component sub-scores at BL, M3, M6, M9, M12 and M24 (mean, SD)
Abbreviations: ADRCs, adipose-derived regenerative cells; ADSCs, adipose-derived stem cells; R, reference; FA, first author; BL, baseline; W6, 6 weeks post treatment; M3/M6/M9/M12/M24, three/six/nine/twelve/24 months post-treatment; LFU, last follow-up (range, M14–M24; mean: M19.8); SD, standard deviation; and CI, confidence interval.
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Schmitz, C.; Alt, C.; Pearce, D.A.; Furia, J.P.; Maffulli, N.; Alt, E.U. Methodological Flaws in Meta-Analyses of Clinical Studies on the Management of Knee Osteoarthritis with Stem Cells: A Systematic Review. Cells 2022, 11, 965. https://doi.org/10.3390/cells11060965

AMA Style

Schmitz C, Alt C, Pearce DA, Furia JP, Maffulli N, Alt EU. Methodological Flaws in Meta-Analyses of Clinical Studies on the Management of Knee Osteoarthritis with Stem Cells: A Systematic Review. Cells. 2022; 11(6):965. https://doi.org/10.3390/cells11060965

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Schmitz, Christoph, Christopher Alt, David A. Pearce, John P. Furia, Nicola Maffulli, and Eckhard U. Alt. 2022. "Methodological Flaws in Meta-Analyses of Clinical Studies on the Management of Knee Osteoarthritis with Stem Cells: A Systematic Review" Cells 11, no. 6: 965. https://doi.org/10.3390/cells11060965

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