Stem Cell Injections in Knee Osteoarthritis a Systematic Review of the Literature

i Introduction

Knee osteoarthritis is a chronic degenerative bone metabolic disease that commonly occurs in eye-aged and older adults; it affects patients' daily activities and fifty-fifty causes disability.^[1,2] Its clinical features mainly include cartilage degenerative lesions, with clinical manifestations such as joint swelling, pain, and deformity. Thus, the main therapeutic purposes of knee osteoarthritis are to reduce or eliminate hurting, correct joint deformities, and amend articulation part through cartilage repair.^[3]

In recent years, replacement of damaged articular cartilage past chondrocytes or cartilage tissue has been considered a potential approach for treating human knee osteoarthritis. Studies have shown that it is feasible to induce homo pluripotent stalk cells to differentiate into chondrocytes; therefore, stalk cell therapy has go a new method for local treatment of knee osteoarthritis. For example, mesenchymal stem cells (MSCs) have multi-directional differentiation potential and can be differentiated into osteoblasts and chondrocytes nether specific induction weather in vitro and in vivo, thereby repairing bone and articular cartilage.^[4,v] However, in that location is still a dispute on the clinical effects of stem cells,^[6–eight] for which a multitude of clinical trials and meta-analyses have been conducted.^[9,10]

Nosotros herein present a meta-analysis of the controversial efficacy and safety of stem jail cell therapy as a clinical treatment of knee joint osteoarthritis. This written report is markedly distinguished from previous meta-analyses^[9,10] considering it focused on os marrow MSCs, peripheral claret stem cells, and amniotic fluid complimentary stem cells. In improver, we used updated data from several latest high-level randomized controlled trials (RCTs).^[11,12] This meta-analysis is expected to provide an show of the efficacy of stalk cell therapy as a conservative handling of knee osteoarthritis.

2 Methods

All analyses were based on previous published studies; thus, no ethical approval and patient consent are required.

2.1 Written report selection

In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement,^[13] 2 researchers independently screened the literature, likewise as extracted and cross-checked the relevant information. If disagreements occurred, a decision regarding data extraction was made by a third researcher.

2.2 Search strategy

We conducted the search in PubMed (1970-May 2019), Embase (1970-May 2019), and The Cochrane Library (1970-May 2019) databases for relevant manufactures, with "stem cells" and "osteoarthritis" every bit search terms. We too manually screened relevant Chinese and English language journals and reference lists to include potential studies. The search strategy for PubMed is detailed herein equally an example: ((("Stem Cells"[Mesh]) OR ((((((((((((((Cell, Stalk[Title/Abstract]) OR Stem Jail cell[Title/Abstract]) OR Progenitor Cells[Championship/Abstract]) OR Jail cell, Progenitor[Championship/Abstruse]) OR Cells, Progenitor[Title/Abstruse]) OR Progenitor Cell[Title/Abstract]) OR Mother Cells[Title/Abstract]) OR Cell, Female parent[Title/Abstract]) OR Cells, Mother[Championship/Abstruse]) OR Mother Prison cell[Title/Abstract]) OR Colony-Forming Unit[Title/Abstract]) OR Colony Forming Unit[Championship/Abstract]) OR Colony-Forming Units[Title/Abstract]) OR Colony Forming Units[Title/Abstract]))) AND ((((((((((((((Osteoarthritides[Title/Abstract]) OR Osteoarthrosis[Title/Abstract]) OR Osteoarthroses[Title/Abstract]) OR Arthritis, Degenerative[Title/Abstract]) OR Arthritides, Degenerative[Title/Abstract]) OR Degenerative Arthritides[Championship/Abstruse]) OR Degenerative Arthritis[Championship/Abstruse]) OR Osteoarthrosis Deformans[Championship/Abstruse]) OR Polyarthritides[Title/Abstract]) OR Arthritides[Championship/Abstract]) OR Polyarthritis[Title/Abstract]) OR Arthritis[Title/Abstract])) OR "Osteoarthritis"[Mesh]).

2.3 Eligibility criteria

The written report inclusion criteria included:

• (ane) studies involving patients with knee osteoarthritis;
• (2) studies including stalk cell therapy as the test group, as well as placebo, hyaluronic acid, and steroid treatments as the control groups;
• (three) RCTs;
• (4) studies that used at least one of the following indicators: Visual Counterpart Scale (VAS) score, Western Ontario and McMaster Universities (WOMAC) subscale, International Articulatio genus Documentation Committee (IKDC) score, and incidence of adverse events.

Studies were ineligible if they met any of the following conditions:

• (1) studies that used animals or cadavers every bit research objects;
• (2) studies that were unable to extract or catechumen valid data;
• (iii) retrospective studies, literature reviews, or briefing papers with no total text.

2.4 Data extraction

Data were extracted independently by 2 researchers using a predesigned data sheet. Valid information were converted as per the Cochrane Handbook for Systematic Reviews of Interventions,^[14] in the case where standard deviation could not exist acquired. If disagreements occurred, the decision regarding data extraction was done past the third reviewer. Each RCT was concurrently assessed with take chances of bias.

2.5 Outcome measures

• VAS is a scoring scale that intuitively quantifies the intensity of pain in the knee joint. A lower score indicates milder pain.
• The WOMAC subscale is a rating calibration that assesses the construction, stiffness, and role of the knee in hurting A lower score indicates ameliorate knee status.
• IKDC is a subjective scale for assessing the knee articulation. A higher score indicates amend symptoms, functions, and physical activities of the knee joint.
• Adverse events refer to treatment-related adverse reactions, including joint effusion, stiffness, and hurting.

2.half-dozen Statistical analysis

Statistical analysis was conducted using the RevMan 5.3 software (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). The chi-square test was used to assess inter-study heterogeneity. I² > 50% indicated heterogeneity. A random effects model was used; otherwise, a fixed furnishings model was used. Relative chance and standardized mean difference were used for assessing binary variables and continuous variables, respectively. The 95% confidence interval estimates and hypothesis testing results for each variable were listed in a forest plot. For each endpoint with high heterogeneity, a sensitivity analysis, in which the included studies were removed one at a fourth dimension, was conducted to screen the source of heterogeneity. A publication bias assessment using a funnel plot was performed if there were no less than 10 studies included.

iii Results

iii.1 Literature search

We retrieved 7054 relevant articles, and ultimately included 9 RCTs^{[11,12,15–21]} involving 399 patients (Fig. 1). In the studies by Kuah,^[12] Lamo-Espinosa,^[xvi] and Thomas Vangsness et al,^[xix] in that location were 2 parallel test groups, namely the high- and depression-dose groups, in comparison with the control group. Therefore, for each study mentioned to a higher place, we conducted statistical analyses in 2 RCTs: high-dose vs control and low-dose vs command.

Effigy 1:

Flowchart of literature retrieval.

3.2 Written report characteristics

There were 203 patients in the stem cell therapy grouping and 196 patients in the control group. The specific features and Jadad scores of the patients^[22,23] are listed in Table 1. The Jadad scale is a vii-point calibration that includes random sequence generation, randomized hiding, blind method, withdrawal, and dropout.

Table 1:

Chief characteristics of all the eligible studies included in the analysis.

3.3 Clinical outcomes

3.iii.i VAS

From baseline to 3 months, 4 studies^{[12,xv,16,20]} were included, involving 6 RCTs with 87 patients in the stem cell group and 79 patients in the control group Fig. two. In that location was no heterogeneity (I² = 0%) between the studies; thus, the fixed furnishings model was used for the analysis. Co-ordinate to Figure 2, SMD (standardized mean difference) = −0.36, 95% CI (confidence interval)[−0.67, −0.05], and P = .02. The VAS score in the stem jail cell group was significantly lower than that in the command group.

Figure 2:

Forest plot of the change of VAS score. VAS = visual analogue scale score.

From baseline to 6 months, 4 studies^{[12,15,16,20]} were included, involving 6 RCTs with 87 patients in the stem prison cell group and 79 patients in the control group. Considering there was a high heterogeneity (I² = 86%) between the studies, the study by Bhattacharya et al^[20] was removed from the sensitivity assay, and the I² value was reduced to 0%. The stock-still effects model was used. According to Figure 2, SMD = −0.86, 95% CI [−1.21, −0.52], and P < .00001. The VAS score in the stem jail cell group was significantly lower than that in the control group.

From baseline to 12 months, 3 studies^[12,16,21] were included, involving 5 RCTs with 51 patients in the stem cell grouping and 43 patients in the control group. There was a depression heterogeneity (I^two = eight%) betwixt the studies, and thus the stock-still effects model was used. According to Figure 2, SMD = −0.86, 95% CI [−1.xxx, −0.43], and P = 0.0001. The VAS score in the stem cell group was significantly lower than that in the command group.

three.3.2 WOMAC-Pain

From baseline to 3 months, two studies^[12,16] were included, involving four RCTs with 36 patients in the stalk cell group and 28 patients in the command group Fig. iii. There was a low heterogeneity (I² = twoscore%) between the studies, and thus the fixed effects model was used. According to Figure iii, SMD = −0.22, 95% CI [−0.73, 0.30], and P = .41. There was no meaning difference in WOMAC-Pain score between the groups.

Figure 3:

Woods plot of the modify of WOMAC-Pain score. WOMAC = Western Ontario and McMaster Universities subscore.

From baseline to six months, 2 studies^[12,xvi] were included, involving four RCTs with 36 patients in the stem cell grouping and 28 patients in the control grouping. There was a low heterogeneity (I² = 48%) between the studies, and thus the stock-still furnishings model was used. According to Figure iii, SMD = −0.08, 95% CI [−0.59, 0.44], and P = .77. There was no significant difference in WOMAC-Hurting score betwixt the groups.

From baseline to 12 months, 3 studies^[12,16] were included, involving 4 RCTs with 43 patients in the stem cell group and 39 patients in the control group. There was no heterogeneity (I² = 0%) betwixt the studies, and thus the stock-still effects model was used. According to Figure 3, SMD = −0.09, 95% CI [−0.53, 0.36], and P = .70. In that location was no significant difference in WOMAC-Hurting score between the groups.

three.3.3 WOMAC-Stiffness

From baseline to three months, 2 studies^[12,sixteen] were included, involving 4 RCTs with 36 patients in the stalk cell group and 28 patients in the control group Fig. 4. There was no heterogeneity (I^two = 0%) betwixt the studies, and the fixed furnishings model was used. According to Effigy four, SMD = −0.51, 95% CI [−1.02, 0.01], and P = .05. There was no meaning divergence in WOMAC-Stiffness score betwixt the groups.

Figure four:

Forest plot of the change of WOMAC-Stiffness score. WOMAC = Western Ontario and McMaster Universities subscore.

From baseline to half-dozen months, two studies^[12,16] were included, involving four RCTs with 36 patients in the stem jail cell grouping and 28 patients in the control group. There was a low heterogeneity (I² = 36%) between the studies, and the stock-still effects model was used. According to Figure four, SMD = −0.25, 95% CI [−0.76, 0.27], and P = .35. There was no meaning difference in WOMAC-Stiffness score between the groups.

From baseline to 12 months, 2 studies^[12,16] were included, involving 4 RCTs with 36 patients in the stem cell group and 28 patients in the control group. At that place was a depression heterogeneity (I² = 9%) betwixt the studies, and the fixed effects model was used. According to Figure iv, SMD = −0.46, 95% CI [−0.98, 0.05], and P = .08. There was no significant departure in WOMAC-Stiffness score between the groups.

3.3.four WOMAC-Function

From baseline to 3 months, 2 studies^[12,16] were included, involving four RCTs with 36 patients in the stem jail cell grouping and 28 patients in the control group Fig. 5. There was no heterogeneity (I² = 0%) betwixt the studies, and the stock-still effects model was used. According to Effigy 5, SMD = 0.xv, 95% CI [−0.35, 0.66], and P = .55. There was no significant difference in WOMAC-Function score between the groups.

Figure 5:

Forest plot of the modify of WOMAC-Function. WOMAC = Western Ontario and McMaster Universities subscore.

From baseline to 6 months, 2 studies^[12,16] were included, involving iv RCTs with 36 patients in the stem prison cell group and 28 patients in the command grouping. There was a low heterogeneity (I² = 29%) between the studies, and the fixed effects model was used. Co-ordinate to Figure 5, SMD = 0.43, 95% CI [−0.09, 0.95], and P = .i. There was no meaning deviation in WOMAC-Role score betwixt the groups.

From baseline to 12 months, ii studies^[12,sixteen] were included, involving four RCTs with 36 patients in the stalk cell group and 28 patients in the control group. In that location was no heterogeneity (I² = 0%) between the studies, and the fixed furnishings model was used. According to Effigy 5, SMD = 0.18, 95% CI [−0.33, 0.68], and P = .49. There was no significant divergence in WOMAC-Part score between the groups.

3.3.5 IKDC

From baseline to 6 months, ii studies^[17,18] were included, involving 2 RCTs with 53 patients in the stem cell group and 52 patients in the control grouping Fig. 6. In that location was a loftier heterogeneity (I² = 51%) between the studies, and the random effects model was used. According to Effigy 6, SMD = 0.16, 95% CI [−0.39,0.72], and P = .56. In that location was no pregnant difference in IKDC score betwixt the groups.

Figure 6:

Forest plot of the alter of IKDC score. IKDC = International Knee Documentation Committee.

From baseline to 12 months, 2 studies^[17,18] were included, involving 2 RCTs with 53 patients in the stem jail cell group and 52 patients in the control group. There was a high heterogeneity (Iⁱⁱ = 83%) between the studies, and the random effects model was used. According to Figure 6, SMD = 0.36, 95% CI [−0.58, 1.31], and P = .45. There was no significant deviation in IKDC score between the groups.

From baseline to 24 months, ii studies^[17,18] were included, involving 2 RCTs with 53 patients in the stem cell grouping and 52 patients in the control group. There was a high heterogeneity (I^two = 75%) between the studies, and the random effects model was used. According to Effigy 6, SMD = 0.53, 95% CI [−0.25, 1.32], and P = .eighteen. There was no significant divergence in IKDC score between the groups.

iii.3.half-dozen Adverse events

At that place were 2 included studies,^[11,12] involving three RCTs with 28 patients in the stalk cell group and 20 patients in the control group Fig. 7. There was a high heterogeneity (Iⁱⁱ = 73%) betwixt the studies, and thus the random effects model was used. According to Figure seven, SMD = i.54, 95% CI [0.57, four.19], and P = .40. There was no significant divergence in incidence of agin events between the groups.

Figure 7:

Woods plot of the change of adverse events.

four Discussion

iv.1 Central findings

Changes in VAS and IKDC scores from baseline to 24 months were superior in the stem cell group than in the control group, whereas there were no statistical differences in the changing trend of other indicators between the 2 groups, including the changes in IKDC scores at 6 months, IKDC score at 12 months, WOMAC-Hurting score, WOMAC-Stiffness score, WOMAC-Function score, WOMAC-Pain score, and incidence of adverse events.

Hurting relief is key to treating knee osteoarthritis, with VAS scores as an important endpoint for pain assessment. Kuah et al^[12] institute that relative to placebo, stem cell therapy considerably relieved hurting at iii, vi, and 12 months after handling. This conclusion has been confirmed in our meta-analysis. Nosotros found that the VAS scores in the stem jail cell grouping were significantly reduced at each visit signal. Inflammatory response is known as i of the causes of pain. MSCs tin can release anti-inflammatory factors, thereby relieving pain. Lamo-Espinosa et al^[16] believed that stem cells accept a paracrine function and their anti-inflammatory properties contribute to pain relief. In add-on, studies accept found that in an acute renal failure model, MSCs can promote recovery of renal part by releasing anti-inflammatory factors and inhibiting production of pro-inflammatory cytokines, such every bit interleukin-1β, tumor necrosis factor, and interferon-γ.^[24] Similar findings were observed in a pulmonary fibrosis model, in which MSCs release IL-one receptor antagonist (IL-1RA) to inhibit interleukin-1α-producing T cells and TNF-producing macrophages, indicating that MSCs have anti-inflammatory properties.^[25] WOMAC-Pain scores showed no statistical difference between the 2 groups at each visit point, but these data regarding WOMAC-Pain score were obtained only from 3 studies;^[12,xvi,21] therefore, further studies with larger sample sizes are warranted to verify these findings.

Functional improvement of the articulatio genus joint is one of the ultimate purposes of knee osteoarthritis treatment. In this study, we used WOMAC-Stiffness, WOMAC-Function, and IKDC scores to comprehensively appraise knee articulation role. Statistical analysis results showed that there was no significant difference between the 2 groups in IKDC scores at 6 and 12 months, as well every bit in WOMAC-Stiffness and WOMAC-Part scores at each visit point. Studies accept establish that mesenchymal stem cell implantation achieves meliorate outcomes in patients with grade iii knee osteoarthritis than those in patients with grade iv articulatio genus osteoarthritis.^[26] We thus concluded that treatment with MSCs are effective in preventing or limiting the progression of knee osteoarthritis at the early on stage. In the studies by Kuah^[12] and Lamo-Espinosa et al,^[16] patients with grade three osteoarthritis or college accounted for 75% and over eighty% of the total patients, respectively. Virtually patients adult knee osteoarthritis at the middle and belatedly stages, for whom treatment with MSCs had no significant efficacy and was not conducive to functional recovery. Moreover, in most tissue engineering methods, MSCs are combined with jail cell scaffolds containing chondrogenic growth factors to form fully functional hyaline cartilage. Such a regimen is ordinarily used in small-animal models of surgically induced cartilage or osteochondral defects, but cannot be used for repairing large-area cartilage defects associated with knee osteoarthritis.^[27] In addition, Centeno,^[28] Emadedin,^[29] and Vangsness et al^[19] pointed out that treatment with approximately ii × 10^seven stem cells can afford expert clinical results. Kuah^[12] and Lamo-Espinosa et al^[16] reported that a stem prison cell dose of lower or college than 2 × x⁷ may also impact the therapeutic efficacy of stem cells. In add-on, the modify in IKDC score at 24 months was higher in the stem cell group than in the control group; withal, these data were extracted from merely two studies. Therefore, farther investigation with a larger sample size is warranted.

For agin events, we sent an e-mail to the authors of the relevant enquiry^{[eighteen,19,21]} to obtain information on the number of patients who experienced treatment-related agin events, including arthralgia, articulation effusion, and joint stiffness, in both the stalk cell and control groups. Because of the lack of response from the other studies, only two studies^[11,12] were included, involving 3 RCTs. There were no statistical differences in adverse events between the 2 groups, indicating that stalk cell treatment has no obvious side furnishings. A study addressing 87 patients with lupus erythematosus^[thirty] showed no agin events associated with transplantation after iv years of follow-up. Similarly, no graft-related adverse events occurred in many patients undergoing stem jail cell therapy for other diseases.^[31–35] These findings indicated that the human trunk has good tolerance to MSCs, and that stalk cell treatment has no significant side effects.

four.2 Limitations

Differences in the original RCT protocols led to bereft representation of some consequence indicators. Thus, high-quality, large-scale RCTs are required to verify our findings. In add-on, in that location was no compatible standard in the preparation and utilise of stem cells, which may cause certain heterogeneity.

5 Conclusion

Compared to traditional methods, stem cell treatment has a certain superiority as a conservative treatment of knee osteoarthritis, in terms of markedly reducing pain without inducing side effects.

Author contributions

Conceptualization: Rui Huang.

Data curation: Rui Huang, Wei Li, Ying Zhao.

Formal analysis: Rui Huang, Wei Li, Ying Zhao, Fan Yang.

Investigation: Rui Huang, Wei Li, Ying Zhao.

Methodology: Rui Huang, Wei Li, Fan Yang.

Project administration: Meng Xu.

Software: Rui Huang, Wei Li, Ying Zhao, Fan Yang.

Supervision: Rui Huang, Wei Li, Ying Zhao, Meng Xu.

Validation: Ying Zhao, Fan Yang, Meng Xu.

Visualization: Rui Huang, Wei Li, Fan Yang.

Writing – original draft: Rui Huang, Wei Li.

Writing – review & editing: Ying Zhao, Meng Xu.

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Keywords:

knee joint osteoarthritis; meta-analysis; stem cell therapy

Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.

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